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STIM1 as a key regulator for Ca2+ homeostasis in skeletal-muscle development and function

STIM1 as a key regulator for Ca2+ homeostasis in skeletal-muscle development and function 2+ Stromal interaction molecules (STIM) were identified as the endoplasmic-reticulum (ER) Ca sensor controlling 2+ 2+ 2+ store-operated Ca entry (SOCE) and Ca -release-activated Ca (CRAC) channels in non-excitable cells. STIM 2+ proteins target Orai1-3, tetrameric Ca -permeable channels in the plasma membrane. Structure-function analysis revealed the molecular determinants and the key steps in the activation process of Orai by STIM. Recently, STIM1 was found to be expressed at high levels in skeletal muscle controlling muscle function and properties. Novel STIM targets besides Orai channels are emerging. Here, we will focus on the role of STIM1 in skeletal-muscle structure, development and function. The molecular mechanism underpinning skeletal-muscle physiology points toward an essential role for STIM1-controlled SOCE to 2+ drive Ca /calcineurin/nuclear factor of activated T cells (NFAT)-dependent morphogenetic remodeling programs 2+ and to support adequate sarcoplasmic-reticulum (SR) Ca -store filling. Also in our hands, STIM1 is transiently up-regulated during the initial phase of in vitro myogenesis of C2C12 cells. The molecular targets of STIM1 in these cells likely involve Orai channels and canonical transient receptor potential (TRPC) channels TRPC1 and TRPC3. The fast kinetics of SOCE activation in skeletal muscle seem to depend on the triad-junction formation, favoring a pre- 2+ localization and/or pre-formation of STIM1-protein complexes with the plasma-membrane Ca -influx channels. 2+ 2+ Moreover, Orai1-mediated Ca influx seems to be essential for controlling the resting Ca concentration and for 2+ 2+ proper SR Ca filling. Hence, Ca influx through STIM1-dependent activation of SOCE from the T-tubule system 2+ 2+ may recycle extracellular Ca losses during muscle stimulation, thereby maintaining proper filling of the SR Ca stores and muscle function. Importantly, mouse models for dystrophic pathologies, like Duchenne muscular 2+ 2 dystrophy, point towards an enhanced Ca influx through Orai1 and/or TRPC channels, leading to Ca -dependent apoptosis and muscle degeneration. In addition, human myopathies have been associated with dysfunctional SOCE. Immunodeficient patients harboring loss-of-function Orai1 mutations develop myopathies, 2+ while patients suffering from Duchenne muscular dystrophy display alterations in their Ca -handling proteins, including STIM proteins. In any case, the molecular determinants responsible for SOCE in human skeletal muscle and for dysregulated SOCE in patients of muscular dystrophy require further examination. 2+ Review proteins as the endoplasmic-reticulum (ER) Ca sensor 2+ 2+ STIM is the ER Ca sensor that controls Orai-mediated and Orai proteins [5-7] as the Ca -permeable store- 2+ 2+ 2+ 2+ store-operated Ca influx operated Ca channel or Ca -release activated Ca For about 20 years after the initial concept of store-oper- (CRAC) channel [8,9]. In mammals, two STIM genes, 2+ ated Ca entry (SOCE) was proposed by Putney [1,2], STIM1 and STIM2,and threeORAIgenes, ORAI1, the molecular candidates underpinning SOCE remained ORAI2 and ORAI3, have been identified [5-7]. Different elusive. In 2005 and 2006, key players for SOCE in non- reports confirmed that STIM1 and Orai1 are the molecu- excitable cells were identified via RNAi screens in Droso- lar candidates for currents with the electrophysiological phila [3] and HeLa cells [4], which elucidated STIM properties of the CRAC channel [10-12]. These proper- 2+ ties include a high selectivity for Ca over monovalent + + 2+ ions, like Na and K , and a single-channel Ca conduc- * Correspondence: geert.bultynck@med.kuleuven.be Laboratory of Molecular and Cellular Signaling, Department Molecular Cell tance of about 30 fS, which is about 100 times smaller Biology, K.U. Leuven, Campus Gasthuisberg O/N-1 bus 802, Herestraat 49, BE- 2+ than the conductance of L-type Ca channels [13,14]. 3000 Leuven, Belgium © 2011 Kiviluoto et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 2 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 STIM1 is predominantly located in the ER, the main the order of tens of seconds and involves local diffusion 2+ intracellular Ca store [4,15-17]. The ER-resident in the ER membranes, while interaction with specific STIM1 controls Orai function by activating these chan- lipids or proteins may facilitate the accumulation of ER/ 2+ nels upon ER Ca -store depletion [3,12,17-19]. Recently, plasma-membrane contact sites [4,16,20]. Two factors the different steps involved in the STIM1-dependent acti- seem to contribute to STIM1 relocalization: i) protein- 2+ vation of Ca influx upon store depletion have been lipid interactions, mediated by the interaction of the identified [15,16,20,21]. These steps include the sensing polybasic C-terminus of STIM1 with plasmalemmal 2+ 2+ of Ca depletion from the ER, dissociation of Ca from phospholipids like phosphatidylinositol 4,5-bisphosphate the EF-hand motif of STIM1, the rapid oligomerization and phosphatidylinositol 3,4,5-trisphosphate, and ii) pro- of STIM1, the translocation of STIM1 into punctae con- tein-protein interactions, mediated by the direct interac- sisting of close ER/plasma-membrane junctions and the tion of STIM1 with the C-terminus of Orai [20,25-28]. 2+ activation of plasma-membrane Ca -influx channels (see The latter interactions are proposed to contribute to [13,14] for recent reviews). the recruitment of Orai1 to ER/plasma-membrane junc- STIM1 (approximately 75 kDa) contains an intraluminal tions. Indeed, C-terminal truncation of Orai1 fails to co- region of approximately 22 kDa, a single transmembrane localize with STIM1 punctae and hence fails to mediate domain and a cytosolic region of approximately 51 kDa. CRAC currents upon store depletion [29,30]. A final 2+ The functional intraluminal ER Ca sensor of STIM1 is step in the activation process is the opening of the tetra- 2+ 2+ the first of two EF-hand domains (EF1; aa 63-96), which meric, Ca -selective Orai1 channels. In vitro Ca -flux precedes a second EF-hand domain (EF2; aa 97-128) and a assays revealed that Orai1 channels are directly gated by sterile a-motif domain (SAM; aa 131-200) [13,22]. The STIM1 [31]. The N-terminal cytosolic domain of Orai1 cytosolic domain consists of two or three coiled-coil seems critical for Orai1-channel opening [30], possibly domains within an ezrin-radixin moesin (ERM) domain, a involving a direct binding of STIM1 to aa 65-91 of serine/proline-rich (S/P) domain and a polybasic lysine- Orai1 [26,29,31]. Recently, the minimal region of STIM1 rich (KKK) domain. Structural analysis of the recombi- involved in CRAC activation was identified as the nantly expressed EF-SAM domain (aa 58-201) revealed CRAC-activating domain (CAD, aa 342-448), also 2+ that Ca is bound to the first EF-hand domain. EF-SAM known as the STIM1-Orai1-activating region (SOAR, aa 2+ exists in a monomeric state when Ca is bound because 344-442) [26,32-34]. of close interaction of the paired EF hands and SAM Very recently, Orai1 channels were shown to be 2+ 2+ [22,23]. When Ca dissociates, protein unfolding triggers directly activated by the SPCA2, a Ca pump belonging 2+ major structural rearrangements of EF-SAM and the accu- to the secretory-pathway Ca ATPases [35]. SPCA2 2+ mulation of dimer and aggregated forms of EF-SAM are expression potentiated Ca influx through Orai1 chan- observed [22,23]. In vitro experiments revealed a K of nels, independently of STIM proteins or SPCA2 Ca 2+ + about 500-600 μMforCa binding to EF-SAM [23], -ATPase activity. The mechanism involves a two-step 2+ 2+ which is in the range of Ca concentration ([Ca ]) in the activation mechanism and interaction of two parts of ER [21]. SPCA2: binding of the N-terminal region of SPCA2 to 2+ Ca dissociation from EF1 of STIM1 causes its oligo- Orai1 enables SPCA2’s C-terminus to access and activate merization [22,23] and underpins the sequential changes Orai1 [35]. These findings are clinically relevant, since 2+ upon ER Ca -store depletion [20]. Mutations in EF1 SPCA2 is up-regulated in breast tumors and SPCA2 2+ disrupting the Ca -binding properties of STIM1 or knockdown decreases tumorigenicity. mutations in EF2 and SAM domain destabilizing the STIM2 is very similar to STIM1 in basic structure and interaction between the EF-hand domains and SAM, functional properties [4,36]. STIM2 senses luminal ER 2+ 2+ result in a constitutively active STIM1 and activation of Ca via two EF-hands. Ca dissociation from STIM2 Orai proteins, resembling their state during depleted ER leads to a conformational change, oligomerization and 2+ Ca stores [4,17]. Oligomerization of STIM1 is closely redistribution to ER/plasma-membrane contact sites [4]. related to activation of CRAC, since artificial oligomeri- The redistribution of STIM2 seems to occur at higher ER 2+ zation of the STIM1 cytosolic domains was sufficient to [Ca ], that is, at smaller decreases in ER, than the redis- 2+ 2+ trigger punctae formation and Ca influx [21]. These tribution of STIM1 [Ca ] [37]. In this perspective, results indicate that the oligomerization of STIM1 is the STIM2 has been identified in an siRNA screen as a criti- 2+ 2+ switch that controls SOCE upon ER Ca -store depletion cal feedback regulator of basal cytosolic and ER [Ca ] via STIM1/Orai1 clustering at ER/plasma-membrane [37]. Knockdown of STIM2 markedly lowers the basal 2+ junctions [21]. cytosolic and ER [Ca ], while knockdown of STIM1 has Upon STIM1 oligomerization, STIM1 redistributes to less effect. However, these features may be dependent on 2+ sites of close apposition of ER and plasma membrane the cell type and/or levels of STIM2, since basal [Ca ]as 2+ [15,16,24]. The kinetics of STIM1 redistribution is in well as the thapsigargin-releasable Ca did not differ Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 3 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 between wild-type mouse embryonic fibroblast (MEF) Canonical transient receptor potential (TRPC) channels cells and MEF cells deficient for STIM2 [38]. Similar Other candidates for SOCE include TRPC channels findings were observed using an overexpression [25,49]. Biochemical and functional experiments revealed that STIM1 directly interacts with TRPC chan- approach, in which STIM2 overexpression increased 2+ nels through electrostatic interaction, which involves the basal cytosolic [Ca ], markedly more than STIM1 over- K864/K865 in the polybasic lysine-rich region of STIM1 expression. Consistent with these findings, small reduc- 2+ and two negative charges that are conserved in all tions in ER [Ca ]caused STIM2, but not STIM1, TRPC channels, that is, D639/D640 in TRPC1 and translocation and redistribution to punctae, with subse- 2+ D697/D698 in TRPC3 [50]. STIM1 was shown to quent activation of Ca influx [37]. While both STIM1 2+ and STIM2 have been implicated in triggering Ca directly bind and regulate TRPC1, TRPC4 and TRPC5, 2+ influx following receptor-mediated ER Ca -store deple- while indirect actions of STIM1 on TRPC3 and TRPC6 -/- tion [37,39], STIM1 cells displayed more severe defects have been proposed [49]. STIM1-dependent gating of -/- in SOCE than STIM2 cells [38,39]. From agonist- TRPC channels seem to differ from their gating of Orai 2+ -/- -/- induced Ca release in STIM1 and STIM2 cells, it channels, pointing towards an independent gating was found that STIM2, but not STIM1, is dispensable for mechanism of TRPCs versus Orai channels by STIM1 2+ agonist-induced Ca signaling [38]. Nevertheless, the [50]. Nevertheless, the regulation of TRPC channels by sustained nuclear localization of NFAT and production STIM1 has been questioned in a very diligent study per- -/- of cytokines are severely hampered in STIM2 Tcells formed by the Putney lab [51], in which endogenous [39]. and ectopic TRPC1-, TRPC3-, TRPC5-, TRPC6- and 2+ The fundamental biological role of STIM/Orai sig- TRPC7-mediated Ca entry was unaffected by increased naling is indicated by the fact that recessive mutations or decreased STIM1 levels. A detailed discussion on the in STIM or Orai affecting their molecular function role of STIM1 in regulating Orai versus TRPC channels lead to severe hereditary immunodeficiency in humans can be found in a recent review [52]. 2+ [13]. Different mutations in STIM1 as well as Orai1 Arachidonate-regulated Ca -selective (ARC) channel leading to loss-of-functionorloss-of-expressionof Another target of STIM1 is the ARC channel, a receptor- 2+ operated Ca -entry channel whose activation is comple- these proteins have been identified in immunodeficient tely independent of store depletion or of translocation of patients [5,40-42]. Importantly, these defects can be ER-resident STIM1 [53,54]. It is proposed that a fraction overcome by STIM1 or Orai1 overexpression, but not of STIM1 constitutively residing at the plasma membrane by STIM2 or Orai2/3, indicating a predominant role 2+ is responsible for the regulation of the activity of the for STIM1/Orai1 in T-cell Ca -signaling function. ARC channels, since antibodies targeting plasmalemmal Loss of STIM1/Orai1 signaling in patients results in severe T-cell immunodeficiency and concomitant viral, STIM1 or mutating its N-linked glycosylation sites essen- bacterial and fungal infections [41-44]. Strikingly, a tial for its cell-surface expression inhibited ARC-channel congenital, nonprogressive myopathy is consistently activity. Recent work identified the molecular architec- observed in infant patients, indicating that STIM1 not ture of ARC channels, revealing a pentameric organiza- only plays a crucial role in T-cell activation and prolif- tion consisting of three Orai1 and two Orai3 subunits eration, but also in skeletal-muscle function and/or [55].Thisdeviatesfromthe tetrameric structure of Orai development (see part 3) [42]. channels mediating CRAC currents. Adenylate cyclase (AC) Other targets of STIM proteins A recent study revealed a novel role for STIM1 where it A detailed discussion on STIM targets can be found in participated in the store-operated recruitment of AC 2+ [13]. [56]. Indeed, depleting ER Ca stores led to the recruit- 2+ Microtubule-plus-end-tracking protein EB1 ment of AC to the intracellular Ca stores, resulting in STIM1 is recruited by end-binding protein-1 (EB1) to increased cAMP levels and enhanced signaling by pro- sites of physical contact between growing microtubule tein kinase A. This process was shown to be indepen- 2+ tips and ER [45,46]. However, the contribution of micro- dent of increases in cytosolic [Ca ], but required the 2+ tubule-associated STIM1 to Ca signaling is not clear. translocation of STIM1. This study therefore points out that STIM1 may be an important integrator molecule Preventing STIM1 localization at the microtubule does 2+ that mediates cross-talk between Ca -dependent signal- not directly affect SOCE [45] and microtubules are not ing and cAMP-dependent signaling. Recently, STIM1- essential for initial CRAC channel gating in T cells and mediated store-operated cAMP signaling has been mast cells [47,48]. Indirect effects of the association of 2+ implicated in the downstream effects of Ca signaling STIM1 with the microtubule may be caused by remo- induced by eicosapentaenoic acid, an omega-3 polyunsa- deling of the ER or ER/plasma-membrane contact sites turated fatty acid present in fish oil [57]. or the availability of STIM1. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 4 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ + The L-type Ca channel Cav1.2 the SR by repetitive high-K stimulation in the presence of 2+ In addition to the well-described Orai targets of STIM1, sarcoplasmic/endoplasmic-reticulum Ca ATPase two very recent studies identified the voltage-operated (SERCA) inhibitors triggered SOCE with the same charac- 2+ Ca channel Cav1.2 as a novel target of STIM1 [58,59]. teristicsasthe CRAC current. This pathwayisdistinct 2+ STIM1 targeted the a1c pore-forming subunit via a from the excitation-coupled Ca entry, which is store- direct interaction, thereby imposing an inhibitory con- independent [62]. Both pathways consist of distinct mole- 2+ 2+ trol over Cav1.2 upon ER Ca -store depletion, indepen- cular components and activation mechanisms [62]. Ca dently of Orai1-channel activity or changes in cytosolic entry is important for store repletion [69], limiting fatigue 2+ [Ca ]. The mechanism involves the direct binding of under conditions of extensive exercise [70], activation of CAD or SOAR to a region encompassing aa 1809-1908, NFAT [63,71] and muscle differentiation [72]. Hence, it is 2+ located in the C-terminus of Cav1.2. becoming increasingly clear that dysregulation of Ca Importantly, while CAD or SOAR activates Orai1- entry may lead to severe muscle pathologies [73-75]. mediated currents, they inhibit Cav1.2-mediated cur- In general, we will limit our discussion to SOCE and we 2+ rents. The interaction of STIM1 with the C-terminus of will refer to other reviews for excitation-coupled Ca Cav1.2 is critical for its inhibition. This process is inde- entry [76,77]. pendent of functional Orai1-channel activity, but Orai1 Four models for SOCE in skeletal muscle have been may help STIM1-mediated Cav1.2 inhibition by trapping proposed, including the conformation coupling between STIM1 in punctae that contain Cav1.2 channels, thereby i) ryanodine receptors (RyRs) and TRPCs, ii) inositol recruiting STIM1 in the vicinity of Cav1.2 channels. In 1,4,5-trisphosphate receptors (IP Rs) and TRPCs, addition, STIM1 expression seems to regulate the iii) STIM1 and Orai1 and iv) STIM1 and TRPC chan- plasma-membrane level of Cav1.2 [59]. Overexpression nels [76]. Figure 2 shows the molecular determinants of STIM1 caused a prominent decrease in the amount involved in SOCE in skeletal muscle with indication of of Cav1.2 at the plasma membrane, leading to STIM1/ the outside-inside coupling between the dihydropyridine Cav1.2 co-localization in intracellular vesicles and the receptor (DHPR), the skeletal-muscle type-1 RyR (RyR1) internalization of the channels. and the inside-outside SOCE-coupling mechanisms via The molecular targeting of STIM1 in Cav1.2 and STIM1/Orai1 and STIM1/TRPC. 2+ Orai1-related Ca -influx pathways may be the molecu- Different studies proposed a role for conformational lar switch that accounts for the reciprocal regulation of coupling of RyRs to TRPCs, thereby activating SOCE 2+ voltage-gated Ca influx (inhibition) and store-operated through TRPC channels [71,73,78]. However, RyRs are 2+ Ca influx (activation) [58,59]. Interestingly, only exci- likely not essential for SOCE in skeletal muscle, since 2+ table cells are able to increase cytosolic [Ca ]in myotubes of mice lacking RyR1/RyR3 still display pro- response to membrane depolarization, although immune minent SOCE [62,70]. Consistent with this, Lee and 2+ cells (T cells, B cells, dendritic cells and mast cells) also et al. did not find any role for TRPC3 in Ca entry in 2+ express voltage-gated Ca channels [60,61]. In contrast, skeletal muscle although its expression level increased only non-excitable cells display prominent CRAC-chan- during differentiation [79]. The authors proposed that nel activity upon store depletion, while SOCE is only a the functional interaction between RyR1 and TRPC3 2+ 2+ minor component of Ca influx in excitable cells enhances RyR1 Ca -release-channel activity and is thus 2+ [62,63]. However, excitable cells, like smooth-muscle required for adequate SR Ca release. cells [64,65], neurons [66] and skeletal-muscle cells [63], Another candidate proposed was the coupling between do express STIM1. The high expression level of STIM1 IP Rs and TRP-family members [80,81], like TRPC3 in skeletal muscle is supported by data obtained from [82]. However, the expression level of IP Rs in myotubes BioGPS (http://biogps.gnf.org/), an online gene annota- is relatively low and their localization is rather around tion portal (Figure 1) [67,68]. Since Cav1.2 and Orai the nuclear envelope than at the SR terminal cisternae 2+ activate different downstream Ca -signaling cascades (TC) [83,84]. 2+ that control growth [65], differentiation [63] and cell The identification of STIM1 as the ER Ca -sensor death [66], it is likely that STIM1 is a novel key player protein and its conformational coupling to Orai1 chan- with different functions in these cell types. nels controlling SOCE in T lymphocytes spurred the idea that STIM1/Orai1 may be the molecular players STIM1 in skeletal muscle underlying SOCE also in skeletal muscle. Different lines SOCE mechanism in skeletal muscle of evidence support the idea that STIM1 is critical for SOCE in skeletal muscle was originally described in a SOCE in skeletal muscle: i) STIM1 and Orai1 are highly study from Kurebayashi and Ogawa [69]. They discovered expressed in skeletal muscle (Figure 1) [63,85], ii) in thin muscle-fiber bundles of the extensor digitorum STIM1 is pre-localized at the SR junctions with the longus (EDL) muscle of adult mice, that the depletion of T-tubule system which contains pre-localized Orai1 Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 5 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 Figure 1 Tissue distribution of Stim1, Stim2, Orai1-3 and Trpc1 in mouse. Data were extracted from the BioGPS database (http://biogps.gnf. org/) and represent the mRNA expression patterns in selected mouse tissues [67,68]. Stim1 is strongly expressed in skeletal muscle and mast cells, while Stim2 exhibits a relatively higher expression level in all tissues tested with pronounced expression in salivary-gland tissue. Orai1 expression is stronger in skeletal muscle, while there is low expression of all Orai in other tissues presented here. Trpc1 expression is relatively low in both heart and skeletal-muscle tissue, but higher in tissue of the central nervous system, such as in the cerebellum. These patterns do not necessarily reflect the expression at the protein level or the situation in humans, but provide a good view of the patterns observed in mouse models. [63,85], iii) mice lacking STIM1 or Orai1 display myopa- activation of TRPC channels [63]. These observations are thy [63], iv) severe combined immunodeficiency (SCID) in line with evidence obtained from myoblasts, which dis- patients characterized by loss-of-function mutations in played a decrease in SOCE upon repression of TRPC1 STIM1/Orai1 signaling display skeletal-muscle myopathy expression, thereby affecting myoblast migration and dif- [5], and v) knockdown of STIM1 or expression of the ferentiation [87]. However, while mice lacking TRPC1 dominant negative Orai1 E106Q caused a marked display a muscle phenotype with muscle fibers that have decline in SOCE in skeletal-muscle myotubes [62]. a decreased cross-sectional area, a reduced force genera- Besides Orai channels, a role for a conformational cou- tion, a decline in the level of myofibrillar proteins and a pling between STIM1 and TRPC channels in skeletal decreased resistance towards muscle fatigue, the role of muscle can however not be excluded. TRPC1 and TRPC3 TRPC1 in adult fibers seemed independent of the Ca channels have been shown to be expressed in skeletal -store content [88]. The work of Gailly and others indi- muscle and have been implicated in SOCE in lympho- cates that the role of TRPC1 in SOCE is dependent on cytes [25]. Moreover, STIM1/Orai1/TRPC1-ternary com- factors that differ among myoblasts and adult fibers plexes have been shown to assemble during store [87,88]. A pivotal role for the a-isoform of the inhibitor depletion, thereby contributing to SOCE [49,50,86]. The of myogenic family (I-mfa) has been proposed, since C-terminal domain of STIM1 has been shown to directly I-mfa binds and inhibits TRPC1 and myogenic factors 2+ bind and activate TRPC1 upon ER Ca -store depletion. interfere with these complexes to alleviate TRPC1 inhibi- Furthermore, in a recent study using whole-cell patch- tion by I-mfa [89,90]. Hence, in myoblasts, TRPC1 may clamp recordings approximately 60% of primary drive the onset of differentiation through a store- myotubes displayed an inwardly rectifying current with controlled mechanism, while in adult fibers TRPC1 may characteristics typical for CRAC current, while approxi- sustain endurance by maintaining force production upon mately 40% of myotubes displayed linear current-voltage repeated stimulation and proper muscle development relationships, which may be related to store-operated through a store-independent mechanism. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 6 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 Figure 2 Regulators of SOCE in skeletal muscle. At the triad junction, the voltage-sensitive DHPR (Cav1.1) and RyR physically interact. 2+ Depolarization of the plasma membrane causes activation of DHPR and subsequent opening of intracellular Ca -release channels, like the most abundant RyR isoform in skeletal muscle, RyR1. In addition, STIM1 monomers and/or oligomers accumulate at the terminal cisternae of the SR, thereby being in close proximity or in complex with Orai1. This pre-localization of STIM1 with Orai1 likely accounts for the fast-activation kinetics 2+ of SOCE. Furthermore, it may also account for a basal Ca influx through Orai1 channels in resting conditions. As a consequence, STIM1/Orai1 2+ 2+ complexes are an integral part of the Ca -homeostasis mechanisms responsible for maintaining proper SERCA1-mediated filling of the SR Ca 2+ stores and sustaining resting [Ca ] in the cytosol. The highly specialized and structural organization of the triad in close proximity of the SR to 2+ plasma-membrane SOCE, which involves junctophilin, seems to be essential for proper STIM1/Orai1-mediated Ca homeostasis. A similar 2+ mechanism involving TRPC channels and STIM1 oligomers have also been implicated in Ca -influx mechanisms in the skeletal muscle, although STIM1-dependent regulation of TRPCs is a matter of debate. Abbreviations: DHPR, dihydropyridine receptor; RyR, ryanodine receptor; SOCE, store- 2+ operated Ca entry; STIM, stromal interaction molecule; SR, sacroplasmic reticulum; TRPC, canonical transient receptor potential. 2+ STIM1/Orai1 pre-localization in skeletal muscle and loaded with Ca underpins the fast kinetics (Figure 2). consequences for SOCE activation The pre-localization of STIM1 in the SR at triad junctions While the molecular determinants responsible for SOCE was observed in differentiated myotubes of the C2C12 cell are very similar among T lymphocytes and skeletal-muscle line as well as in native skeletal muscle from the hind cells, there are also some striking differences, which may limbs of adult mice [63,85]. The exact molecular architec- be related to the pre-localization of STIM1/Orai1 and the ture of the inactive STIM1/Orai1 complexes in resting 2+ putative contribution of voltage-gated Ca channels in skeletal-muscle cells remains to be elucidated. Two mod- 2+ the targeting of STIM1 to the TC/T-tubule junctions. els that allow for rapid SOCE activation upon SR Ca - Indeed, a clear distinction between SOCE in T lympho- store depletion were proposed by Dirksen [76]. In model cytes and in skeletal muscle is the kinetics of CRAC- 1, STIM1 monomers are localized in the vicinity of inac- channel activation. In T lymphocytes, the kinetics of tive Orai1 channels at the triad junctions. A decrease in 2+ 2+ SOCE activation by store depletion is relatively slow with the SR [Ca ] will cause rapid dissociation of Ca from a delay of tens of seconds between store depletion and STIM1, resulting in conformational changes in STIM1, its SOCE. In contrast, in skeletal muscle the local activation oligomerization and activation of the pre-localized Orai1 of SOCE by store depletion is almost instant (less than 1 channels. In model 2, STIM1 exists in pre-formed com- second delay) and graded in nature, as shown in recent plexes with the C-terminal region of inactive Orai1 chan- 2+ studies by Launikonis [91,92]. Hence, it was proposed that nels, which remain silent until a decrease in SR [Ca ] pre-localization of STIM1 and Orai1 at TC/T-tubule junc- triggers conformational changes in STIM1 and direct acti- 2+ tions under basal conditions when SR stores are fully vation of Orai1-mediated Ca influx, for example through Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 7 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 an interaction of STIM1 with the N-terminus of Orai1. (a1s) differs in properties with a1c, it is possible that The latter would allow for an ultra-fast, efficient and STIM1 interacts with both. tightly controlled activation of Orai1. STIM1 in physiological signaling In any case, the spatial organization of triad-junction Recently, it became clear that SOCE plays a prominent structure, which allows close contacts between the TC of role in muscle development and muscle function and theSRand thetransversetubular invaginationsofthe that STIM1 hereby has a central role [63,93,96,97] plasma membrane, seems to be the key for efficient (Figure 3). For example, mice deficient in STIM1 signal- SOCE in skeletal muscle [93]. Indeed, disrupting the ing displayed defects in muscle differentiation and con- triad structure in skeletal-muscle fibers by acute suppres- tractile activity [63]. Homozygous STIM1-deficient sion of junctophilin 1/2, a protein responsible for form- neonatal mice died from a perinatal myopathy, whereas ing the close contacts between the intracellular stores STIM1-haploinsufficient mice displayed increased sus- and the plasma membrane (Figure 2), leads to reduced ceptibility to fatigue. These data indicate that STIM1 2+ 2+ SOCE, a decrease in the SR Ca content and altered caf- controls both chronic Ca -controlled signaling pro- 2+ feine-triggered RyR-mediated Ca response. Hence, cesses, like muscle differentiation and remodeling structural properties of the triad junctions seem to be through the activation of a genetic program, as well as 2+ responsible for the efficient coupling of retrograde signal- acute Ca -signaling processes such as muscle contrac- ing from the SR to T-tubules, thereby controlling SOCE, tion, by supporting the adequate function of the con- 2+ and overall Ca homeostasis and muscle physiology. tractile system under conditions of prolonged motor- These features may be important in explaining the effect nerve activity. of pathophysiological mutations in junctophilins or Underlying these phenomena is STIM1-dependent altered junctophilin-expression profiles that are asso- activation of NFAT in skeletal muscle, which drives myo- ciated with cardiac failure or muscle aging [94,95]. Very genesis and muscle differentiation [63]. It has been recently, reduced SOCE in junctophilin-1 knock out known for a long time that a dramatic remodeling of 2+ myotubes was associated with a decline in STIM1/Orai1- Ca -transport mechanisms underlies and accompanies 2+ expression levels and a reduced resting cytosolic [Ca ] skeletal-muscle differentiation. Differentiation of BC H1 2+ 2+ and SR Ca content [96]. Using a Ca -entry blocker, cells to a muscular phenotype was characterized by a 2+ 2+ BTP2, Eltit and co-workers showed that Ca influx was decrease in IP -induced Ca release and an increase in 2+ 2+ 2+ essential for maintaining proper resting [Ca ], since Ca -pump activity as well as in caffeine-induced Ca treating wild-type myotubes with BTP2 caused a decrease release [98]. Also during C2C12 differentiation from 2+ in SOCE and in resting [Ca ], resembling the situation myoblasts to multinucleated myotubes, IP R-expression 2+ in junctophilin-1 knock out myotubes [96]. Since differ- levels declined, while the expression levels of RyR1 Ca - 2+ 2+ ent Ca -entry mechanisms may account for this phar- release channels and SERCA2a/SERCA1 Ca pumps macological effect, the authors elegantly used the dramatically augmented [99]. A recent study of Stiber dominant negative Orai1 form, Orai1 E190Q. Strikingly, et al. [63] now adds STIM1 as another molecular factor, expression of Orai1 E190Q was sufficient to inhibit whose expression level increases and whose localization SOCE in wild-type myotubes and to decrease the resting changes from perinuclear to cell peripheral upon differ- 2+ [Ca ], while it had no effect in junctophilin-1 knock out entiation of C2C12 myoblasts into myotubes. These myotubes. As a consequence, wild-type myotubes expres- molecular findings correlate with the increased rate of 2+ 2+ sing Orai1 E190Q displayed a reduced SR Ca content. Ca influx in these cells upon thapsigargin-induced SR 2+ Hence, this study is one of the first to show that Orai1- Ca -store depletion. mediated SOCE is critical to control resting cytosolic Independently, we have examined STIM1- and STIM2- 2+ 2+ 2 [Ca ]andSR Ca content. This further supports the protein levels together with the expression of other Ca concept that SOCE is an essential feature for proper -handling proteins, like Orai1, SERCA1, SERCA2a, RyRs muscle function, not only during conditions of intensive and IP Rs in differentiating C2C12 cells (Figures 4A and stimulation, but also during resting conditions. 4B). We could confirm the up-regulation of STIM1 and It is also conceivable that other plasma-membrane Orai1 in C2C12 cells undergoing differentiation. However channels may contribute to the pre-localization of we observed a transient up-regulation of STIM1, while STIM1 to the TC/t-tubule junctions. The identification Orai1 is permanently augmented. Strikingly, the maximal of the a1c subunit of the voltage-gated Cav1.2 channel STIM1 levels correlate with the up-regulation of Orai1, as a novel target of STIM1 [58,59] may point towards a but precede the up-regulation of SERCA1, SERCA2a and 2+ more general role for voltage-gated Ca channels to RyR. In contrast, STIM2 levels did not significantly change target STIM1 in spatially or functionally restricted during C2C12 differentiation, suggesting a selective role 2+ domains. Although the DHPR L-type Ca -channel for STIM1 in skeletal-muscle differentiation. STIM1 Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 8 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ Figure 3 Schematic overview of the physiological role of SOCE in skeletal muscle and pathophysiological consequences of Ca -influx 2+ dysregulation based on mouse-model studies. STIM1-controlled Ca influx, either through Orai1 or TRPC channels, ought to be tightly 2+ 2+ regulated for proper muscle development and function. STIM1-gated Orai1-mediated Ca influx seems to be a requisite for proper Ca 2+ 2+ homeostasis in the skeletal muscle, maintaining resting cytosolic [Ca ] sufficiently high and adequately filling the SR Ca stores. This constitutes 2+ an essential mechanism that compensates for Ca losses to the extracellular space. Importantly, these phenomena may not only act during periods of intense stimulation, but may also be required during basal conditions and regular muscle function. On the one hand, suppressing 2+ Ca influx, for example in STIM1-deficient muscle fibers, leads to improper muscle development and function. This is likely due to hampered 2+ activation of NFAT-dependent signaling and defective expression of Ca -handling proteins, such as SERCAs and RyRs, as well as other proteins involved in muscle contraction. On the other hand, events such as mutations in dystrophin or overexpression of TRPC channels, lead to muscle 2+ 2+ dystrophy and degeneration, likely due to mitochondrial Ca overload and Ca -dependent activation of the apoptotic program. Abbreviations: 2+ NFAT, nuclear factor of activated T cells; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic-reticulum Ca -ATPase; SR, sacroplasmic reticulum; STIM, stromal interaction molecule; TRPC, canonical transient receptor potential. gt/gt up-regulation seems to be a very proximal event in skele- domain of STIM1 [63]. Most homozygous STIM1 tal-muscle differentiation. Nevertheless, this transient mice died at a neonatal stage. However, surviving mice STIM1 up-regulation seems to correlate with the observa- displayed decreased body weight, impaired muscle forma- tions of Stiber et al. in muscle formation during develop- tion and increased fatigue. Studies revealed that the SOC ment in vivo [63]. currents in response to thapsigargin were completely It is possible that the transient STIM1 up-regulation, abolished in primary myotubes deficient of STIM1. which seems to occur as an intermediate step between STIM1 deficiency caused a severe impairment of the myogenin and SERCA/RyR up-regulation, is needed for skeletal-muscle structure and function. STIM1 loss also 2+ increasing Ca influx and is required for driving the resulted in increased central nucleation, a reduced muscle 2+ remodeling of the Ca -handling proteins through cross-sectional area, swollen mitochondria and a decline 2+ Ca -dependent NFAT signaling (Figure 4C). Indeed, in the muscle-specific proteins in the SR, like SERCA1 Stiber et al. have shown that STIM1 silencing with and myosin heavy chain. In addition, the levels of MyoD, short hairpin RNA decreased basal NFAT trans-activa- one of the master regulatory genes that controls muscle tion in differentiated myotubes, while constitutively differentiation, were lower in the muscle of STIM1- active STIM1 expression increased basal NFAT trans- deficient mice. At the functional level, loss of STIM1 led activation [63]. Furthermore, NFAT is known to con- to a decrease in the maximal tetanic force and in the fati- trol muscle formation through morphogenetic events gue resistance. The latter could be attributed to an 2+ 2+ that depend on Ca -dependent signaling through the impaired SR Ca -store filling in the myotubes. After on- 2+ activation of calcineurin/NFAT [100,101]. going depolarization pulses, the content of the SR Ca gt/gt The critical role of STIM1 in skeletal-muscle develop- stores was severely reduced in STIM1 myotubes in ment was further demonstrated by Stiber et al. using a contrast to their wild-type counterparts. This indicates gene trap approach resulting in the expression of STIM1/ that STIM1-controlled SOCE is required to refill the inter- gt 2+ LacZ-fusion proteins (STIM1 ), which contained the N- nal SR Ca stores during repeated stimulations. The latter terminal EF-SAM domain and the transmembrane has been confirmed by another study showing the rapid Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 9 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ Figure 4 Expression of Ca -handling proteins including STIM1, STIM2 and Orai1 during myogenic differentiation of C2C12 cells.A: Representative panel of Western blots for each protein of interest in lysates from C2C12 cells in an undifferentiated state and different stages of differentiation. B: Graph represents the average expression of three independent biological samples (mean ± S.E.M.) of C2C12 cells undergoing differentiation. All values were normalized to GAPDH, which was used as a loading control. C: A model for key proteins involved in the proper remodeling of myoblasts into myotubes, based on previous reports [99] and own data. The expression pattern of myogenin, taken from the study of MacLennan and co-workers [99], was up-regulated starting from day 1 of myoblast differentiation, which would mark the first wave of differentiation [99]. Orai1, SERCA2a and RyR1 started to emerge at day 3, while cells exhibit a transient cardiac phenotype. Interestingly, we also observed an even shorter transient of STIM1 up-regulation, which seemed to decline at the same time as SERCA1 levels increased. Remarkably, while STIM1 was transiently up-regulated, STIM2 did not significantly alter and Orai1 continued to increase during differentiation. Materials and methods: Cells were collected 0, 1, 3 or 5 days after replacing myoblast culture medium with myotube differentiation medium [99,113]. Cell lysates were analyzed for protein expression by Western blot and expression was each time normalized to GAPDH expression. Signals were detected with ECF and analyzed with ImageJ. Antibodies were from ProSci Inc., Poway, CA, USA (Orai1), Sigma, St Louis, MO, USA (STIM2 and GAPDH), Abnova, Taipei City, Taiwan (STIM1) and Thermo Scientific, Rockford, IL, USA (SERCA1 and RyR). The SERCA2a and IP R1 antibodies are described elsewhere [114,115]. Abbreviations: ECF, enhanced chemifluorescence; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IP R, 2+ inositol 1,4,5-trisphosphate receptor; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic-reticulum Ca -ATPase; STIM, stromal interaction molecule. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 10 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ efflux of Ca in the T-tubule system upon muscle-cell molecular basis for these shifts in threshold may be asso- depolarizations [91]. A critical function of STIM1 in SR ciated with the dramatic increase in STIM1/Orai-protein 2+ Ca -store filling in human skeletal muscle needs to be levels found in the mdx muscle fibers [106]. Interestingly, confirmed. However, the fact that SCID patients carrying these data may correlate with our observations suggesting loss-of-protein expression mutations in the STIM1 gene, a transient up-regulation of STIM1 during muscle differ- manifest atrophy of the type-II skeletal-muscle fibers entiation, while a permanent up-regulation of STIM1 may resulting in severe chronic pulmonary disease [41], sup- contribute to deleterious muscle events. 2+ ports the concept that STIM1-mediated SOCE plays a Independently of the mechanism, preventing Ca 2+ critical role in sustaining proper SR Ca -store filling and influx may be beneficial and holds potential for future skeletal-muscle function in humans. therapeutic strategies to tackle muscular dystrophy STIM1 in pathophysiological signaling either by targeting STIM1/Orai1 or TRPC channels, While STIM1 and SOCE seem to be essential for skele- since both channel complexes have been shown to be 2+ tal-muscle development, excessive store-operated Ca implicated and/or up-regulated in Duchenne muscular influx may underpin pathological conditions, like Duch- dystrophy models [75,106]. All studies seem to agree on enne muscular dystrophy [74]. A crucial feature of this the fact that excessive SOCE is an early event in this disease is defective expression of dystrophin. Myotubes pathology and that inhibiting SOCE seems to be benefi- 2+ lacking functional dystrophin display altered Ca cial. This paradigm is supported by different studies: dynamics, characterized by exaggerated SOCE [74,102]. i) TRPC suppression rescues muscular dystrophic fea- The latter may be responsible for the observed sustained tures in mouse models [75]; ii) blockers of stretch-acti- 2+ 2+ cytosolic Ca transients and increased Ca uptake by vated channels prevent muscle degeneration in mdx the mitochondria. Importantly, re-introduction of mini- mice [107]; iii) inhibitors of phospholipase A2, which is 2+ dystrophin reduces Ca entry to its normal level, which overexpressed in skeletal muscle of a mouse model for 2+ leads to shorter Ca transients and decreased mito- Duchenne muscular dystrophy, attenuate the exagger- 2+ chondrial Ca uptake [74]. Although these studies did ated SOCE and the subsequent muscle damage [102]. 2+ not clarify the involvement or role of STIM1, they point Furthermore, while reducing Ca influx may be criti- 2+ towards a critical regulation of proper SOCE for the cal for targeting this pathology, inhibiting Ca release physiological function of skeletal cells. Indeed, SOCE from the ER has also been shown to be beneficial [108]. apparently needs to be tightly regulated, since sup- For instance, overexpression of anti-apoptotic Bcl-2 pre- 2+ pressed as well as exaggerated SOCE underpin skeletal- vented IP R-mediated Ca release [109,110] and subse- 2+ muscle dysfunction [63,74]. An elegant study recently quent mitochondrial Ca overload, thereby protecting 2+ published by the Molkentin lab indicated that increased dystrophic muscle cells against Ca -dependent apopto- 2+ Ca entry by itself is sufficient to induce muscular dys- sis [108]. Hence, a concerted strategy to alleviate muscu- 2+ trophy in vivo, since transgenic mice overexpressing lar dystrophy likely requires the dampening of both Ca 2+ TRPC3 channels are characterized by features similar to influx as well as ER Ca release. the dystrophic disease models [75]. Finally, it is important to note that most of the evi- 2+ 2+ Different molecular mechanisms of increased Ca entry dence that points towards excessive Ca influx as an underpinning this disease model have been proposed, early event in the development of muscular dystrophy including store-operated and stretch-operated ion chan- has been obtained from mouse models. We need to nels [103]. On the one hand, TRPC channels seem impor- keep in mind that the need and physiological role of tant candidates [75]. Indeed, mdx dystrophic skeletal- SOCE might be different for mouse and human skeletal 2+ muscle fibers displayed increased TRPC-mediated Ca muscle. For instance, a micro-array analysis of human influx [73,75]. Interestingly, TRPC1 has been shown to skeletal-muscle biopsies from control patients and associate with the dystrophin-protein complex [104,105]. Duchenne muscular dystrophy patients (obtained from Moreover, dystrophic skeletal-muscle disease models asso- the Gene Expression Omnibus; http://www.ncbi.nlm.nih. ciated with mutations in the dystrophin or mutations in gov/geo/) indicated that the STIM1-mRNA levels were the delta-Sarcoglycan (Scgd) genes were rescued by trans- not increased, but rather tended to decrease in the mus- gene-mediated inhibition of TRPC channels, thereby redu- cle of the dystrophic patients, while Orai1-mRNA levels 2+ cing Ca influx and preventing the development of were not significantly changed (Figure 5). This seems in muscular-dystrophy features [75]. On the other hand, Lau- contrast with the up-regulation of STIM1 and Orai1 nikonis and co-workers demonstrated that while SOCE and the increased SOCE reported in mouse models for functions normally in mdx muscle fibers, the thresholds Duchenne muscular dystrophy. These contrasting find- for activation and deactivation of SOCE have been shifted ings may indicate that mechanisms underpinning SOCE 2+ to higher SR [Ca ] [106]. This may contribute to higher are differently affected in the human muscular patholo- 2+ Ca influx during long periods of stimulation. The gies versus the mouse models for these pathologies. In Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 11 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ Figure 5 Gene expression involved in Ca and/or contractility. Plots represent gene expression in quadriceps skeletal-muscle samples of controls (CTL, n = 10-12) and patients with Duchenne muscular dystrophy (DMD, n = 10 - 12) in arbitrary units (A.U.). Data were obtained from GEO reference series GSE1007 (STIM1, STIM2, ORAI1, ITPR1 and CASQ1) and GSE1004 (TRPC1, ATP2A1, RYR1 and MYH2) [116-118] comparing the mRNA-expression levels in normal and dystrophic patients (http://www.ncbi.nlm.nih.gov/geo/). Graphs represent box plots, indicating the mean th th th th (square symbol), the median (line), the 25 and 75 percentiles (bottom and top of the box), and the 5 and 95 percentiles (whisker range). Strikingly, STIM1-, SERCA1-, RyR1-mRNA levels tended to decline, while STIM2-, TRPC1- and IP R1-mRNA levels tended to increase. Orai1-, calsequestrin-1- and myosin heavy chain-2-mRNA levels did not significantly alter. This seems opposite to what has been observed in mouse 2+ models for Duchenne muscular dystrophy, which displayed excessive Ca influx and up-regulation of STIM1/Orai1 [106]. In human patients 2+ 2+ suffering from Duchenne muscular dystrophy, TRPC1 elevations may account for the increase in Ca influx, leading to Ca -dependent apoptosis and muscle degeneration. This indicates that caution should be taken from extrapolating results from mouse models for pathophysiological conditions to human pathophysiological conditions. Abbreviations indicate the gene names for stromal interaction molecule 1(STIM1), stromal interaction molecule 2 (STIM2), Orai1 (ORAI1), canonical transient receptor potential 1 (TRPC1), sarcoplasmic/endoplasmic- 2+ reticulum Ca -ATPase 1 (ATP2A1), ryanodine receptor 1 (RYR1), inositol 1,4,5-trisphosphate receptor 1 (ITPR1), calsequestrin 1 (CASQ1), and myosin heavy chain IIa (MYH2). addition, the relative importance of STIM1 versus human patients. In any case, it is clear that the role of STIM2 for SOCE in human muscles and their contribu- both STIM proteins for the development of myopathies tion to myopathies may differ among human and mice. in human patients must be further explored. In this respect, Duchenne muscular dystrophy patients Moreover, other mechanisms may account for the 2+ did show an up-regulation of STIM2-mRNA levels, excessive Ca influx that leads to muscle degeneration in 2+ which is activated at more modest decreases in [Ca ] human patients. Therefore, it is important to note that ER than STIM1. Therefore, STIM2 up-regulation may be TRPC1-mRNA levels are also significantly up-regulated in another critical factor that needs to be taken into the patients suffering from muscular dystrophy. Impor- account in the development of muscular dystrophy in tantly, excessive TRPC1 activity has been implicated in Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 12 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ 2+ Attraction Poles Program (Belgian Science Policy; P6/28 to HDS, JBP and LM). spontaneous Ca influx and the activation of Ca -depen- JPD is a Ph.D. fellow of the Agency for Innovation by Science and dent proteolysis, leading to the degradation of cytoskeletal Technology (IWT). The authors wish to thank Dr. Peter Vangheluwe for proteins and the development of myopathies in Homer providing materials. 1-deficient mice [111]. Decreased levels of Homer 1 in Authors’ contributions mdx mouse models may contribute to the reported GB conceived the experiments, analyzed the data and wrote the manuscript. TRPC1 hyperactivity in response to store depletion [73]. SK performed the experiments, analyzed the data and wrote the manuscript. JPD, HDS, LM and JBP discussed the data and revised the manuscript. However, the contribution of STIM1 in this process remains unknown. Competing interests Finally, these micro-array analyses also revealed that The authors declare that they have no competing interests. SERCA1- and RyR1-mRNA levels declined, IP R1- Received: 13 December 2010 Accepted: 4 April 2011 mRNA levels increased and Orai1-, calsequestrin-1- and Published: 4 April 2011 myosin heavy chain-2-mRNA levels did not significantly alter. Changes in IP R-expression level have previously 3 References 1. Putney JW Jr: A model for receptor-regulated calcium entry. 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STIM1 as a key regulator for Ca2+ homeostasis in skeletal-muscle development and function

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Copyright © 2011 by Kiviluoto et al; licensee BioMed Central Ltd.
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Life Sciences; Cell Biology; Developmental Biology; Biochemistry, general; Systems Biology; Biotechnology
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2044-5040
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10.1186/2044-5040-1-16
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21798093
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Abstract

2+ Stromal interaction molecules (STIM) were identified as the endoplasmic-reticulum (ER) Ca sensor controlling 2+ 2+ 2+ store-operated Ca entry (SOCE) and Ca -release-activated Ca (CRAC) channels in non-excitable cells. STIM 2+ proteins target Orai1-3, tetrameric Ca -permeable channels in the plasma membrane. Structure-function analysis revealed the molecular determinants and the key steps in the activation process of Orai by STIM. Recently, STIM1 was found to be expressed at high levels in skeletal muscle controlling muscle function and properties. Novel STIM targets besides Orai channels are emerging. Here, we will focus on the role of STIM1 in skeletal-muscle structure, development and function. The molecular mechanism underpinning skeletal-muscle physiology points toward an essential role for STIM1-controlled SOCE to 2+ drive Ca /calcineurin/nuclear factor of activated T cells (NFAT)-dependent morphogenetic remodeling programs 2+ and to support adequate sarcoplasmic-reticulum (SR) Ca -store filling. Also in our hands, STIM1 is transiently up-regulated during the initial phase of in vitro myogenesis of C2C12 cells. The molecular targets of STIM1 in these cells likely involve Orai channels and canonical transient receptor potential (TRPC) channels TRPC1 and TRPC3. The fast kinetics of SOCE activation in skeletal muscle seem to depend on the triad-junction formation, favoring a pre- 2+ localization and/or pre-formation of STIM1-protein complexes with the plasma-membrane Ca -influx channels. 2+ 2+ Moreover, Orai1-mediated Ca influx seems to be essential for controlling the resting Ca concentration and for 2+ 2+ proper SR Ca filling. Hence, Ca influx through STIM1-dependent activation of SOCE from the T-tubule system 2+ 2+ may recycle extracellular Ca losses during muscle stimulation, thereby maintaining proper filling of the SR Ca stores and muscle function. Importantly, mouse models for dystrophic pathologies, like Duchenne muscular 2+ 2 dystrophy, point towards an enhanced Ca influx through Orai1 and/or TRPC channels, leading to Ca -dependent apoptosis and muscle degeneration. In addition, human myopathies have been associated with dysfunctional SOCE. Immunodeficient patients harboring loss-of-function Orai1 mutations develop myopathies, 2+ while patients suffering from Duchenne muscular dystrophy display alterations in their Ca -handling proteins, including STIM proteins. In any case, the molecular determinants responsible for SOCE in human skeletal muscle and for dysregulated SOCE in patients of muscular dystrophy require further examination. 2+ Review proteins as the endoplasmic-reticulum (ER) Ca sensor 2+ 2+ STIM is the ER Ca sensor that controls Orai-mediated and Orai proteins [5-7] as the Ca -permeable store- 2+ 2+ 2+ 2+ store-operated Ca influx operated Ca channel or Ca -release activated Ca For about 20 years after the initial concept of store-oper- (CRAC) channel [8,9]. In mammals, two STIM genes, 2+ ated Ca entry (SOCE) was proposed by Putney [1,2], STIM1 and STIM2,and threeORAIgenes, ORAI1, the molecular candidates underpinning SOCE remained ORAI2 and ORAI3, have been identified [5-7]. Different elusive. In 2005 and 2006, key players for SOCE in non- reports confirmed that STIM1 and Orai1 are the molecu- excitable cells were identified via RNAi screens in Droso- lar candidates for currents with the electrophysiological phila [3] and HeLa cells [4], which elucidated STIM properties of the CRAC channel [10-12]. These proper- 2+ ties include a high selectivity for Ca over monovalent + + 2+ ions, like Na and K , and a single-channel Ca conduc- * Correspondence: geert.bultynck@med.kuleuven.be Laboratory of Molecular and Cellular Signaling, Department Molecular Cell tance of about 30 fS, which is about 100 times smaller Biology, K.U. Leuven, Campus Gasthuisberg O/N-1 bus 802, Herestraat 49, BE- 2+ than the conductance of L-type Ca channels [13,14]. 3000 Leuven, Belgium © 2011 Kiviluoto et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 2 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 STIM1 is predominantly located in the ER, the main the order of tens of seconds and involves local diffusion 2+ intracellular Ca store [4,15-17]. The ER-resident in the ER membranes, while interaction with specific STIM1 controls Orai function by activating these chan- lipids or proteins may facilitate the accumulation of ER/ 2+ nels upon ER Ca -store depletion [3,12,17-19]. Recently, plasma-membrane contact sites [4,16,20]. Two factors the different steps involved in the STIM1-dependent acti- seem to contribute to STIM1 relocalization: i) protein- 2+ vation of Ca influx upon store depletion have been lipid interactions, mediated by the interaction of the identified [15,16,20,21]. These steps include the sensing polybasic C-terminus of STIM1 with plasmalemmal 2+ 2+ of Ca depletion from the ER, dissociation of Ca from phospholipids like phosphatidylinositol 4,5-bisphosphate the EF-hand motif of STIM1, the rapid oligomerization and phosphatidylinositol 3,4,5-trisphosphate, and ii) pro- of STIM1, the translocation of STIM1 into punctae con- tein-protein interactions, mediated by the direct interac- sisting of close ER/plasma-membrane junctions and the tion of STIM1 with the C-terminus of Orai [20,25-28]. 2+ activation of plasma-membrane Ca -influx channels (see The latter interactions are proposed to contribute to [13,14] for recent reviews). the recruitment of Orai1 to ER/plasma-membrane junc- STIM1 (approximately 75 kDa) contains an intraluminal tions. Indeed, C-terminal truncation of Orai1 fails to co- region of approximately 22 kDa, a single transmembrane localize with STIM1 punctae and hence fails to mediate domain and a cytosolic region of approximately 51 kDa. CRAC currents upon store depletion [29,30]. A final 2+ The functional intraluminal ER Ca sensor of STIM1 is step in the activation process is the opening of the tetra- 2+ 2+ the first of two EF-hand domains (EF1; aa 63-96), which meric, Ca -selective Orai1 channels. In vitro Ca -flux precedes a second EF-hand domain (EF2; aa 97-128) and a assays revealed that Orai1 channels are directly gated by sterile a-motif domain (SAM; aa 131-200) [13,22]. The STIM1 [31]. The N-terminal cytosolic domain of Orai1 cytosolic domain consists of two or three coiled-coil seems critical for Orai1-channel opening [30], possibly domains within an ezrin-radixin moesin (ERM) domain, a involving a direct binding of STIM1 to aa 65-91 of serine/proline-rich (S/P) domain and a polybasic lysine- Orai1 [26,29,31]. Recently, the minimal region of STIM1 rich (KKK) domain. Structural analysis of the recombi- involved in CRAC activation was identified as the nantly expressed EF-SAM domain (aa 58-201) revealed CRAC-activating domain (CAD, aa 342-448), also 2+ that Ca is bound to the first EF-hand domain. EF-SAM known as the STIM1-Orai1-activating region (SOAR, aa 2+ exists in a monomeric state when Ca is bound because 344-442) [26,32-34]. of close interaction of the paired EF hands and SAM Very recently, Orai1 channels were shown to be 2+ 2+ [22,23]. When Ca dissociates, protein unfolding triggers directly activated by the SPCA2, a Ca pump belonging 2+ major structural rearrangements of EF-SAM and the accu- to the secretory-pathway Ca ATPases [35]. SPCA2 2+ mulation of dimer and aggregated forms of EF-SAM are expression potentiated Ca influx through Orai1 chan- observed [22,23]. In vitro experiments revealed a K of nels, independently of STIM proteins or SPCA2 Ca 2+ + about 500-600 μMforCa binding to EF-SAM [23], -ATPase activity. The mechanism involves a two-step 2+ 2+ which is in the range of Ca concentration ([Ca ]) in the activation mechanism and interaction of two parts of ER [21]. SPCA2: binding of the N-terminal region of SPCA2 to 2+ Ca dissociation from EF1 of STIM1 causes its oligo- Orai1 enables SPCA2’s C-terminus to access and activate merization [22,23] and underpins the sequential changes Orai1 [35]. These findings are clinically relevant, since 2+ upon ER Ca -store depletion [20]. Mutations in EF1 SPCA2 is up-regulated in breast tumors and SPCA2 2+ disrupting the Ca -binding properties of STIM1 or knockdown decreases tumorigenicity. mutations in EF2 and SAM domain destabilizing the STIM2 is very similar to STIM1 in basic structure and interaction between the EF-hand domains and SAM, functional properties [4,36]. STIM2 senses luminal ER 2+ 2+ result in a constitutively active STIM1 and activation of Ca via two EF-hands. Ca dissociation from STIM2 Orai proteins, resembling their state during depleted ER leads to a conformational change, oligomerization and 2+ Ca stores [4,17]. Oligomerization of STIM1 is closely redistribution to ER/plasma-membrane contact sites [4]. related to activation of CRAC, since artificial oligomeri- The redistribution of STIM2 seems to occur at higher ER 2+ zation of the STIM1 cytosolic domains was sufficient to [Ca ], that is, at smaller decreases in ER, than the redis- 2+ 2+ trigger punctae formation and Ca influx [21]. These tribution of STIM1 [Ca ] [37]. In this perspective, results indicate that the oligomerization of STIM1 is the STIM2 has been identified in an siRNA screen as a criti- 2+ 2+ switch that controls SOCE upon ER Ca -store depletion cal feedback regulator of basal cytosolic and ER [Ca ] via STIM1/Orai1 clustering at ER/plasma-membrane [37]. Knockdown of STIM2 markedly lowers the basal 2+ junctions [21]. cytosolic and ER [Ca ], while knockdown of STIM1 has Upon STIM1 oligomerization, STIM1 redistributes to less effect. However, these features may be dependent on 2+ sites of close apposition of ER and plasma membrane the cell type and/or levels of STIM2, since basal [Ca ]as 2+ [15,16,24]. The kinetics of STIM1 redistribution is in well as the thapsigargin-releasable Ca did not differ Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 3 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 between wild-type mouse embryonic fibroblast (MEF) Canonical transient receptor potential (TRPC) channels cells and MEF cells deficient for STIM2 [38]. Similar Other candidates for SOCE include TRPC channels findings were observed using an overexpression [25,49]. Biochemical and functional experiments revealed that STIM1 directly interacts with TRPC chan- approach, in which STIM2 overexpression increased 2+ nels through electrostatic interaction, which involves the basal cytosolic [Ca ], markedly more than STIM1 over- K864/K865 in the polybasic lysine-rich region of STIM1 expression. Consistent with these findings, small reduc- 2+ and two negative charges that are conserved in all tions in ER [Ca ]caused STIM2, but not STIM1, TRPC channels, that is, D639/D640 in TRPC1 and translocation and redistribution to punctae, with subse- 2+ D697/D698 in TRPC3 [50]. STIM1 was shown to quent activation of Ca influx [37]. While both STIM1 2+ and STIM2 have been implicated in triggering Ca directly bind and regulate TRPC1, TRPC4 and TRPC5, 2+ influx following receptor-mediated ER Ca -store deple- while indirect actions of STIM1 on TRPC3 and TRPC6 -/- tion [37,39], STIM1 cells displayed more severe defects have been proposed [49]. STIM1-dependent gating of -/- in SOCE than STIM2 cells [38,39]. From agonist- TRPC channels seem to differ from their gating of Orai 2+ -/- -/- induced Ca release in STIM1 and STIM2 cells, it channels, pointing towards an independent gating was found that STIM2, but not STIM1, is dispensable for mechanism of TRPCs versus Orai channels by STIM1 2+ agonist-induced Ca signaling [38]. Nevertheless, the [50]. Nevertheless, the regulation of TRPC channels by sustained nuclear localization of NFAT and production STIM1 has been questioned in a very diligent study per- -/- of cytokines are severely hampered in STIM2 Tcells formed by the Putney lab [51], in which endogenous [39]. and ectopic TRPC1-, TRPC3-, TRPC5-, TRPC6- and 2+ The fundamental biological role of STIM/Orai sig- TRPC7-mediated Ca entry was unaffected by increased naling is indicated by the fact that recessive mutations or decreased STIM1 levels. A detailed discussion on the in STIM or Orai affecting their molecular function role of STIM1 in regulating Orai versus TRPC channels lead to severe hereditary immunodeficiency in humans can be found in a recent review [52]. 2+ [13]. Different mutations in STIM1 as well as Orai1 Arachidonate-regulated Ca -selective (ARC) channel leading to loss-of-functionorloss-of-expressionof Another target of STIM1 is the ARC channel, a receptor- 2+ operated Ca -entry channel whose activation is comple- these proteins have been identified in immunodeficient tely independent of store depletion or of translocation of patients [5,40-42]. Importantly, these defects can be ER-resident STIM1 [53,54]. It is proposed that a fraction overcome by STIM1 or Orai1 overexpression, but not of STIM1 constitutively residing at the plasma membrane by STIM2 or Orai2/3, indicating a predominant role 2+ is responsible for the regulation of the activity of the for STIM1/Orai1 in T-cell Ca -signaling function. ARC channels, since antibodies targeting plasmalemmal Loss of STIM1/Orai1 signaling in patients results in severe T-cell immunodeficiency and concomitant viral, STIM1 or mutating its N-linked glycosylation sites essen- bacterial and fungal infections [41-44]. Strikingly, a tial for its cell-surface expression inhibited ARC-channel congenital, nonprogressive myopathy is consistently activity. Recent work identified the molecular architec- observed in infant patients, indicating that STIM1 not ture of ARC channels, revealing a pentameric organiza- only plays a crucial role in T-cell activation and prolif- tion consisting of three Orai1 and two Orai3 subunits eration, but also in skeletal-muscle function and/or [55].Thisdeviatesfromthe tetrameric structure of Orai development (see part 3) [42]. channels mediating CRAC currents. Adenylate cyclase (AC) Other targets of STIM proteins A recent study revealed a novel role for STIM1 where it A detailed discussion on STIM targets can be found in participated in the store-operated recruitment of AC 2+ [13]. [56]. Indeed, depleting ER Ca stores led to the recruit- 2+ Microtubule-plus-end-tracking protein EB1 ment of AC to the intracellular Ca stores, resulting in STIM1 is recruited by end-binding protein-1 (EB1) to increased cAMP levels and enhanced signaling by pro- sites of physical contact between growing microtubule tein kinase A. This process was shown to be indepen- 2+ tips and ER [45,46]. However, the contribution of micro- dent of increases in cytosolic [Ca ], but required the 2+ tubule-associated STIM1 to Ca signaling is not clear. translocation of STIM1. This study therefore points out that STIM1 may be an important integrator molecule Preventing STIM1 localization at the microtubule does 2+ that mediates cross-talk between Ca -dependent signal- not directly affect SOCE [45] and microtubules are not ing and cAMP-dependent signaling. Recently, STIM1- essential for initial CRAC channel gating in T cells and mediated store-operated cAMP signaling has been mast cells [47,48]. Indirect effects of the association of 2+ implicated in the downstream effects of Ca signaling STIM1 with the microtubule may be caused by remo- induced by eicosapentaenoic acid, an omega-3 polyunsa- deling of the ER or ER/plasma-membrane contact sites turated fatty acid present in fish oil [57]. or the availability of STIM1. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 4 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ + The L-type Ca channel Cav1.2 the SR by repetitive high-K stimulation in the presence of 2+ In addition to the well-described Orai targets of STIM1, sarcoplasmic/endoplasmic-reticulum Ca ATPase two very recent studies identified the voltage-operated (SERCA) inhibitors triggered SOCE with the same charac- 2+ Ca channel Cav1.2 as a novel target of STIM1 [58,59]. teristicsasthe CRAC current. This pathwayisdistinct 2+ STIM1 targeted the a1c pore-forming subunit via a from the excitation-coupled Ca entry, which is store- direct interaction, thereby imposing an inhibitory con- independent [62]. Both pathways consist of distinct mole- 2+ 2+ trol over Cav1.2 upon ER Ca -store depletion, indepen- cular components and activation mechanisms [62]. Ca dently of Orai1-channel activity or changes in cytosolic entry is important for store repletion [69], limiting fatigue 2+ [Ca ]. The mechanism involves the direct binding of under conditions of extensive exercise [70], activation of CAD or SOAR to a region encompassing aa 1809-1908, NFAT [63,71] and muscle differentiation [72]. Hence, it is 2+ located in the C-terminus of Cav1.2. becoming increasingly clear that dysregulation of Ca Importantly, while CAD or SOAR activates Orai1- entry may lead to severe muscle pathologies [73-75]. mediated currents, they inhibit Cav1.2-mediated cur- In general, we will limit our discussion to SOCE and we 2+ rents. The interaction of STIM1 with the C-terminus of will refer to other reviews for excitation-coupled Ca Cav1.2 is critical for its inhibition. This process is inde- entry [76,77]. pendent of functional Orai1-channel activity, but Orai1 Four models for SOCE in skeletal muscle have been may help STIM1-mediated Cav1.2 inhibition by trapping proposed, including the conformation coupling between STIM1 in punctae that contain Cav1.2 channels, thereby i) ryanodine receptors (RyRs) and TRPCs, ii) inositol recruiting STIM1 in the vicinity of Cav1.2 channels. In 1,4,5-trisphosphate receptors (IP Rs) and TRPCs, addition, STIM1 expression seems to regulate the iii) STIM1 and Orai1 and iv) STIM1 and TRPC chan- plasma-membrane level of Cav1.2 [59]. Overexpression nels [76]. Figure 2 shows the molecular determinants of STIM1 caused a prominent decrease in the amount involved in SOCE in skeletal muscle with indication of of Cav1.2 at the plasma membrane, leading to STIM1/ the outside-inside coupling between the dihydropyridine Cav1.2 co-localization in intracellular vesicles and the receptor (DHPR), the skeletal-muscle type-1 RyR (RyR1) internalization of the channels. and the inside-outside SOCE-coupling mechanisms via The molecular targeting of STIM1 in Cav1.2 and STIM1/Orai1 and STIM1/TRPC. 2+ Orai1-related Ca -influx pathways may be the molecu- Different studies proposed a role for conformational lar switch that accounts for the reciprocal regulation of coupling of RyRs to TRPCs, thereby activating SOCE 2+ voltage-gated Ca influx (inhibition) and store-operated through TRPC channels [71,73,78]. However, RyRs are 2+ Ca influx (activation) [58,59]. Interestingly, only exci- likely not essential for SOCE in skeletal muscle, since 2+ table cells are able to increase cytosolic [Ca ]in myotubes of mice lacking RyR1/RyR3 still display pro- response to membrane depolarization, although immune minent SOCE [62,70]. Consistent with this, Lee and 2+ cells (T cells, B cells, dendritic cells and mast cells) also et al. did not find any role for TRPC3 in Ca entry in 2+ express voltage-gated Ca channels [60,61]. In contrast, skeletal muscle although its expression level increased only non-excitable cells display prominent CRAC-chan- during differentiation [79]. The authors proposed that nel activity upon store depletion, while SOCE is only a the functional interaction between RyR1 and TRPC3 2+ 2+ minor component of Ca influx in excitable cells enhances RyR1 Ca -release-channel activity and is thus 2+ [62,63]. However, excitable cells, like smooth-muscle required for adequate SR Ca release. cells [64,65], neurons [66] and skeletal-muscle cells [63], Another candidate proposed was the coupling between do express STIM1. The high expression level of STIM1 IP Rs and TRP-family members [80,81], like TRPC3 in skeletal muscle is supported by data obtained from [82]. However, the expression level of IP Rs in myotubes BioGPS (http://biogps.gnf.org/), an online gene annota- is relatively low and their localization is rather around tion portal (Figure 1) [67,68]. Since Cav1.2 and Orai the nuclear envelope than at the SR terminal cisternae 2+ activate different downstream Ca -signaling cascades (TC) [83,84]. 2+ that control growth [65], differentiation [63] and cell The identification of STIM1 as the ER Ca -sensor death [66], it is likely that STIM1 is a novel key player protein and its conformational coupling to Orai1 chan- with different functions in these cell types. nels controlling SOCE in T lymphocytes spurred the idea that STIM1/Orai1 may be the molecular players STIM1 in skeletal muscle underlying SOCE also in skeletal muscle. Different lines SOCE mechanism in skeletal muscle of evidence support the idea that STIM1 is critical for SOCE in skeletal muscle was originally described in a SOCE in skeletal muscle: i) STIM1 and Orai1 are highly study from Kurebayashi and Ogawa [69]. They discovered expressed in skeletal muscle (Figure 1) [63,85], ii) in thin muscle-fiber bundles of the extensor digitorum STIM1 is pre-localized at the SR junctions with the longus (EDL) muscle of adult mice, that the depletion of T-tubule system which contains pre-localized Orai1 Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 5 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 Figure 1 Tissue distribution of Stim1, Stim2, Orai1-3 and Trpc1 in mouse. Data were extracted from the BioGPS database (http://biogps.gnf. org/) and represent the mRNA expression patterns in selected mouse tissues [67,68]. Stim1 is strongly expressed in skeletal muscle and mast cells, while Stim2 exhibits a relatively higher expression level in all tissues tested with pronounced expression in salivary-gland tissue. Orai1 expression is stronger in skeletal muscle, while there is low expression of all Orai in other tissues presented here. Trpc1 expression is relatively low in both heart and skeletal-muscle tissue, but higher in tissue of the central nervous system, such as in the cerebellum. These patterns do not necessarily reflect the expression at the protein level or the situation in humans, but provide a good view of the patterns observed in mouse models. [63,85], iii) mice lacking STIM1 or Orai1 display myopa- activation of TRPC channels [63]. These observations are thy [63], iv) severe combined immunodeficiency (SCID) in line with evidence obtained from myoblasts, which dis- patients characterized by loss-of-function mutations in played a decrease in SOCE upon repression of TRPC1 STIM1/Orai1 signaling display skeletal-muscle myopathy expression, thereby affecting myoblast migration and dif- [5], and v) knockdown of STIM1 or expression of the ferentiation [87]. However, while mice lacking TRPC1 dominant negative Orai1 E106Q caused a marked display a muscle phenotype with muscle fibers that have decline in SOCE in skeletal-muscle myotubes [62]. a decreased cross-sectional area, a reduced force genera- Besides Orai channels, a role for a conformational cou- tion, a decline in the level of myofibrillar proteins and a pling between STIM1 and TRPC channels in skeletal decreased resistance towards muscle fatigue, the role of muscle can however not be excluded. TRPC1 and TRPC3 TRPC1 in adult fibers seemed independent of the Ca channels have been shown to be expressed in skeletal -store content [88]. The work of Gailly and others indi- muscle and have been implicated in SOCE in lympho- cates that the role of TRPC1 in SOCE is dependent on cytes [25]. Moreover, STIM1/Orai1/TRPC1-ternary com- factors that differ among myoblasts and adult fibers plexes have been shown to assemble during store [87,88]. A pivotal role for the a-isoform of the inhibitor depletion, thereby contributing to SOCE [49,50,86]. The of myogenic family (I-mfa) has been proposed, since C-terminal domain of STIM1 has been shown to directly I-mfa binds and inhibits TRPC1 and myogenic factors 2+ bind and activate TRPC1 upon ER Ca -store depletion. interfere with these complexes to alleviate TRPC1 inhibi- Furthermore, in a recent study using whole-cell patch- tion by I-mfa [89,90]. Hence, in myoblasts, TRPC1 may clamp recordings approximately 60% of primary drive the onset of differentiation through a store- myotubes displayed an inwardly rectifying current with controlled mechanism, while in adult fibers TRPC1 may characteristics typical for CRAC current, while approxi- sustain endurance by maintaining force production upon mately 40% of myotubes displayed linear current-voltage repeated stimulation and proper muscle development relationships, which may be related to store-operated through a store-independent mechanism. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 6 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 Figure 2 Regulators of SOCE in skeletal muscle. At the triad junction, the voltage-sensitive DHPR (Cav1.1) and RyR physically interact. 2+ Depolarization of the plasma membrane causes activation of DHPR and subsequent opening of intracellular Ca -release channels, like the most abundant RyR isoform in skeletal muscle, RyR1. In addition, STIM1 monomers and/or oligomers accumulate at the terminal cisternae of the SR, thereby being in close proximity or in complex with Orai1. This pre-localization of STIM1 with Orai1 likely accounts for the fast-activation kinetics 2+ of SOCE. Furthermore, it may also account for a basal Ca influx through Orai1 channels in resting conditions. As a consequence, STIM1/Orai1 2+ 2+ complexes are an integral part of the Ca -homeostasis mechanisms responsible for maintaining proper SERCA1-mediated filling of the SR Ca 2+ stores and sustaining resting [Ca ] in the cytosol. The highly specialized and structural organization of the triad in close proximity of the SR to 2+ plasma-membrane SOCE, which involves junctophilin, seems to be essential for proper STIM1/Orai1-mediated Ca homeostasis. A similar 2+ mechanism involving TRPC channels and STIM1 oligomers have also been implicated in Ca -influx mechanisms in the skeletal muscle, although STIM1-dependent regulation of TRPCs is a matter of debate. Abbreviations: DHPR, dihydropyridine receptor; RyR, ryanodine receptor; SOCE, store- 2+ operated Ca entry; STIM, stromal interaction molecule; SR, sacroplasmic reticulum; TRPC, canonical transient receptor potential. 2+ STIM1/Orai1 pre-localization in skeletal muscle and loaded with Ca underpins the fast kinetics (Figure 2). consequences for SOCE activation The pre-localization of STIM1 in the SR at triad junctions While the molecular determinants responsible for SOCE was observed in differentiated myotubes of the C2C12 cell are very similar among T lymphocytes and skeletal-muscle line as well as in native skeletal muscle from the hind cells, there are also some striking differences, which may limbs of adult mice [63,85]. The exact molecular architec- be related to the pre-localization of STIM1/Orai1 and the ture of the inactive STIM1/Orai1 complexes in resting 2+ putative contribution of voltage-gated Ca channels in skeletal-muscle cells remains to be elucidated. Two mod- 2+ the targeting of STIM1 to the TC/T-tubule junctions. els that allow for rapid SOCE activation upon SR Ca - Indeed, a clear distinction between SOCE in T lympho- store depletion were proposed by Dirksen [76]. In model cytes and in skeletal muscle is the kinetics of CRAC- 1, STIM1 monomers are localized in the vicinity of inac- channel activation. In T lymphocytes, the kinetics of tive Orai1 channels at the triad junctions. A decrease in 2+ 2+ SOCE activation by store depletion is relatively slow with the SR [Ca ] will cause rapid dissociation of Ca from a delay of tens of seconds between store depletion and STIM1, resulting in conformational changes in STIM1, its SOCE. In contrast, in skeletal muscle the local activation oligomerization and activation of the pre-localized Orai1 of SOCE by store depletion is almost instant (less than 1 channels. In model 2, STIM1 exists in pre-formed com- second delay) and graded in nature, as shown in recent plexes with the C-terminal region of inactive Orai1 chan- 2+ studies by Launikonis [91,92]. Hence, it was proposed that nels, which remain silent until a decrease in SR [Ca ] pre-localization of STIM1 and Orai1 at TC/T-tubule junc- triggers conformational changes in STIM1 and direct acti- 2+ tions under basal conditions when SR stores are fully vation of Orai1-mediated Ca influx, for example through Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 7 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 an interaction of STIM1 with the N-terminus of Orai1. (a1s) differs in properties with a1c, it is possible that The latter would allow for an ultra-fast, efficient and STIM1 interacts with both. tightly controlled activation of Orai1. STIM1 in physiological signaling In any case, the spatial organization of triad-junction Recently, it became clear that SOCE plays a prominent structure, which allows close contacts between the TC of role in muscle development and muscle function and theSRand thetransversetubular invaginationsofthe that STIM1 hereby has a central role [63,93,96,97] plasma membrane, seems to be the key for efficient (Figure 3). For example, mice deficient in STIM1 signal- SOCE in skeletal muscle [93]. Indeed, disrupting the ing displayed defects in muscle differentiation and con- triad structure in skeletal-muscle fibers by acute suppres- tractile activity [63]. Homozygous STIM1-deficient sion of junctophilin 1/2, a protein responsible for form- neonatal mice died from a perinatal myopathy, whereas ing the close contacts between the intracellular stores STIM1-haploinsufficient mice displayed increased sus- and the plasma membrane (Figure 2), leads to reduced ceptibility to fatigue. These data indicate that STIM1 2+ 2+ SOCE, a decrease in the SR Ca content and altered caf- controls both chronic Ca -controlled signaling pro- 2+ feine-triggered RyR-mediated Ca response. Hence, cesses, like muscle differentiation and remodeling structural properties of the triad junctions seem to be through the activation of a genetic program, as well as 2+ responsible for the efficient coupling of retrograde signal- acute Ca -signaling processes such as muscle contrac- ing from the SR to T-tubules, thereby controlling SOCE, tion, by supporting the adequate function of the con- 2+ and overall Ca homeostasis and muscle physiology. tractile system under conditions of prolonged motor- These features may be important in explaining the effect nerve activity. of pathophysiological mutations in junctophilins or Underlying these phenomena is STIM1-dependent altered junctophilin-expression profiles that are asso- activation of NFAT in skeletal muscle, which drives myo- ciated with cardiac failure or muscle aging [94,95]. Very genesis and muscle differentiation [63]. It has been recently, reduced SOCE in junctophilin-1 knock out known for a long time that a dramatic remodeling of 2+ myotubes was associated with a decline in STIM1/Orai1- Ca -transport mechanisms underlies and accompanies 2+ expression levels and a reduced resting cytosolic [Ca ] skeletal-muscle differentiation. Differentiation of BC H1 2+ 2+ and SR Ca content [96]. Using a Ca -entry blocker, cells to a muscular phenotype was characterized by a 2+ 2+ BTP2, Eltit and co-workers showed that Ca influx was decrease in IP -induced Ca release and an increase in 2+ 2+ 2+ essential for maintaining proper resting [Ca ], since Ca -pump activity as well as in caffeine-induced Ca treating wild-type myotubes with BTP2 caused a decrease release [98]. Also during C2C12 differentiation from 2+ in SOCE and in resting [Ca ], resembling the situation myoblasts to multinucleated myotubes, IP R-expression 2+ in junctophilin-1 knock out myotubes [96]. Since differ- levels declined, while the expression levels of RyR1 Ca - 2+ 2+ ent Ca -entry mechanisms may account for this phar- release channels and SERCA2a/SERCA1 Ca pumps macological effect, the authors elegantly used the dramatically augmented [99]. A recent study of Stiber dominant negative Orai1 form, Orai1 E190Q. Strikingly, et al. [63] now adds STIM1 as another molecular factor, expression of Orai1 E190Q was sufficient to inhibit whose expression level increases and whose localization SOCE in wild-type myotubes and to decrease the resting changes from perinuclear to cell peripheral upon differ- 2+ [Ca ], while it had no effect in junctophilin-1 knock out entiation of C2C12 myoblasts into myotubes. These myotubes. As a consequence, wild-type myotubes expres- molecular findings correlate with the increased rate of 2+ 2+ sing Orai1 E190Q displayed a reduced SR Ca content. Ca influx in these cells upon thapsigargin-induced SR 2+ Hence, this study is one of the first to show that Orai1- Ca -store depletion. mediated SOCE is critical to control resting cytosolic Independently, we have examined STIM1- and STIM2- 2+ 2+ 2 [Ca ]andSR Ca content. This further supports the protein levels together with the expression of other Ca concept that SOCE is an essential feature for proper -handling proteins, like Orai1, SERCA1, SERCA2a, RyRs muscle function, not only during conditions of intensive and IP Rs in differentiating C2C12 cells (Figures 4A and stimulation, but also during resting conditions. 4B). We could confirm the up-regulation of STIM1 and It is also conceivable that other plasma-membrane Orai1 in C2C12 cells undergoing differentiation. However channels may contribute to the pre-localization of we observed a transient up-regulation of STIM1, while STIM1 to the TC/t-tubule junctions. The identification Orai1 is permanently augmented. Strikingly, the maximal of the a1c subunit of the voltage-gated Cav1.2 channel STIM1 levels correlate with the up-regulation of Orai1, as a novel target of STIM1 [58,59] may point towards a but precede the up-regulation of SERCA1, SERCA2a and 2+ more general role for voltage-gated Ca channels to RyR. In contrast, STIM2 levels did not significantly change target STIM1 in spatially or functionally restricted during C2C12 differentiation, suggesting a selective role 2+ domains. Although the DHPR L-type Ca -channel for STIM1 in skeletal-muscle differentiation. STIM1 Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 8 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ Figure 3 Schematic overview of the physiological role of SOCE in skeletal muscle and pathophysiological consequences of Ca -influx 2+ dysregulation based on mouse-model studies. STIM1-controlled Ca influx, either through Orai1 or TRPC channels, ought to be tightly 2+ 2+ regulated for proper muscle development and function. STIM1-gated Orai1-mediated Ca influx seems to be a requisite for proper Ca 2+ 2+ homeostasis in the skeletal muscle, maintaining resting cytosolic [Ca ] sufficiently high and adequately filling the SR Ca stores. This constitutes 2+ an essential mechanism that compensates for Ca losses to the extracellular space. Importantly, these phenomena may not only act during periods of intense stimulation, but may also be required during basal conditions and regular muscle function. On the one hand, suppressing 2+ Ca influx, for example in STIM1-deficient muscle fibers, leads to improper muscle development and function. This is likely due to hampered 2+ activation of NFAT-dependent signaling and defective expression of Ca -handling proteins, such as SERCAs and RyRs, as well as other proteins involved in muscle contraction. On the other hand, events such as mutations in dystrophin or overexpression of TRPC channels, lead to muscle 2+ 2+ dystrophy and degeneration, likely due to mitochondrial Ca overload and Ca -dependent activation of the apoptotic program. Abbreviations: 2+ NFAT, nuclear factor of activated T cells; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic-reticulum Ca -ATPase; SR, sacroplasmic reticulum; STIM, stromal interaction molecule; TRPC, canonical transient receptor potential. gt/gt up-regulation seems to be a very proximal event in skele- domain of STIM1 [63]. Most homozygous STIM1 tal-muscle differentiation. Nevertheless, this transient mice died at a neonatal stage. However, surviving mice STIM1 up-regulation seems to correlate with the observa- displayed decreased body weight, impaired muscle forma- tions of Stiber et al. in muscle formation during develop- tion and increased fatigue. Studies revealed that the SOC ment in vivo [63]. currents in response to thapsigargin were completely It is possible that the transient STIM1 up-regulation, abolished in primary myotubes deficient of STIM1. which seems to occur as an intermediate step between STIM1 deficiency caused a severe impairment of the myogenin and SERCA/RyR up-regulation, is needed for skeletal-muscle structure and function. STIM1 loss also 2+ increasing Ca influx and is required for driving the resulted in increased central nucleation, a reduced muscle 2+ remodeling of the Ca -handling proteins through cross-sectional area, swollen mitochondria and a decline 2+ Ca -dependent NFAT signaling (Figure 4C). Indeed, in the muscle-specific proteins in the SR, like SERCA1 Stiber et al. have shown that STIM1 silencing with and myosin heavy chain. In addition, the levels of MyoD, short hairpin RNA decreased basal NFAT trans-activa- one of the master regulatory genes that controls muscle tion in differentiated myotubes, while constitutively differentiation, were lower in the muscle of STIM1- active STIM1 expression increased basal NFAT trans- deficient mice. At the functional level, loss of STIM1 led activation [63]. Furthermore, NFAT is known to con- to a decrease in the maximal tetanic force and in the fati- trol muscle formation through morphogenetic events gue resistance. The latter could be attributed to an 2+ 2+ that depend on Ca -dependent signaling through the impaired SR Ca -store filling in the myotubes. After on- 2+ activation of calcineurin/NFAT [100,101]. going depolarization pulses, the content of the SR Ca gt/gt The critical role of STIM1 in skeletal-muscle develop- stores was severely reduced in STIM1 myotubes in ment was further demonstrated by Stiber et al. using a contrast to their wild-type counterparts. This indicates gene trap approach resulting in the expression of STIM1/ that STIM1-controlled SOCE is required to refill the inter- gt 2+ LacZ-fusion proteins (STIM1 ), which contained the N- nal SR Ca stores during repeated stimulations. The latter terminal EF-SAM domain and the transmembrane has been confirmed by another study showing the rapid Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 9 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ Figure 4 Expression of Ca -handling proteins including STIM1, STIM2 and Orai1 during myogenic differentiation of C2C12 cells.A: Representative panel of Western blots for each protein of interest in lysates from C2C12 cells in an undifferentiated state and different stages of differentiation. B: Graph represents the average expression of three independent biological samples (mean ± S.E.M.) of C2C12 cells undergoing differentiation. All values were normalized to GAPDH, which was used as a loading control. C: A model for key proteins involved in the proper remodeling of myoblasts into myotubes, based on previous reports [99] and own data. The expression pattern of myogenin, taken from the study of MacLennan and co-workers [99], was up-regulated starting from day 1 of myoblast differentiation, which would mark the first wave of differentiation [99]. Orai1, SERCA2a and RyR1 started to emerge at day 3, while cells exhibit a transient cardiac phenotype. Interestingly, we also observed an even shorter transient of STIM1 up-regulation, which seemed to decline at the same time as SERCA1 levels increased. Remarkably, while STIM1 was transiently up-regulated, STIM2 did not significantly alter and Orai1 continued to increase during differentiation. Materials and methods: Cells were collected 0, 1, 3 or 5 days after replacing myoblast culture medium with myotube differentiation medium [99,113]. Cell lysates were analyzed for protein expression by Western blot and expression was each time normalized to GAPDH expression. Signals were detected with ECF and analyzed with ImageJ. Antibodies were from ProSci Inc., Poway, CA, USA (Orai1), Sigma, St Louis, MO, USA (STIM2 and GAPDH), Abnova, Taipei City, Taiwan (STIM1) and Thermo Scientific, Rockford, IL, USA (SERCA1 and RyR). The SERCA2a and IP R1 antibodies are described elsewhere [114,115]. Abbreviations: ECF, enhanced chemifluorescence; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IP R, 2+ inositol 1,4,5-trisphosphate receptor; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic-reticulum Ca -ATPase; STIM, stromal interaction molecule. Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 10 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ efflux of Ca in the T-tubule system upon muscle-cell molecular basis for these shifts in threshold may be asso- depolarizations [91]. A critical function of STIM1 in SR ciated with the dramatic increase in STIM1/Orai-protein 2+ Ca -store filling in human skeletal muscle needs to be levels found in the mdx muscle fibers [106]. Interestingly, confirmed. However, the fact that SCID patients carrying these data may correlate with our observations suggesting loss-of-protein expression mutations in the STIM1 gene, a transient up-regulation of STIM1 during muscle differ- manifest atrophy of the type-II skeletal-muscle fibers entiation, while a permanent up-regulation of STIM1 may resulting in severe chronic pulmonary disease [41], sup- contribute to deleterious muscle events. 2+ ports the concept that STIM1-mediated SOCE plays a Independently of the mechanism, preventing Ca 2+ critical role in sustaining proper SR Ca -store filling and influx may be beneficial and holds potential for future skeletal-muscle function in humans. therapeutic strategies to tackle muscular dystrophy STIM1 in pathophysiological signaling either by targeting STIM1/Orai1 or TRPC channels, While STIM1 and SOCE seem to be essential for skele- since both channel complexes have been shown to be 2+ tal-muscle development, excessive store-operated Ca implicated and/or up-regulated in Duchenne muscular influx may underpin pathological conditions, like Duch- dystrophy models [75,106]. All studies seem to agree on enne muscular dystrophy [74]. A crucial feature of this the fact that excessive SOCE is an early event in this disease is defective expression of dystrophin. Myotubes pathology and that inhibiting SOCE seems to be benefi- 2+ lacking functional dystrophin display altered Ca cial. This paradigm is supported by different studies: dynamics, characterized by exaggerated SOCE [74,102]. i) TRPC suppression rescues muscular dystrophic fea- The latter may be responsible for the observed sustained tures in mouse models [75]; ii) blockers of stretch-acti- 2+ 2+ cytosolic Ca transients and increased Ca uptake by vated channels prevent muscle degeneration in mdx the mitochondria. Importantly, re-introduction of mini- mice [107]; iii) inhibitors of phospholipase A2, which is 2+ dystrophin reduces Ca entry to its normal level, which overexpressed in skeletal muscle of a mouse model for 2+ leads to shorter Ca transients and decreased mito- Duchenne muscular dystrophy, attenuate the exagger- 2+ chondrial Ca uptake [74]. Although these studies did ated SOCE and the subsequent muscle damage [102]. 2+ not clarify the involvement or role of STIM1, they point Furthermore, while reducing Ca influx may be criti- 2+ towards a critical regulation of proper SOCE for the cal for targeting this pathology, inhibiting Ca release physiological function of skeletal cells. Indeed, SOCE from the ER has also been shown to be beneficial [108]. apparently needs to be tightly regulated, since sup- For instance, overexpression of anti-apoptotic Bcl-2 pre- 2+ pressed as well as exaggerated SOCE underpin skeletal- vented IP R-mediated Ca release [109,110] and subse- 2+ muscle dysfunction [63,74]. An elegant study recently quent mitochondrial Ca overload, thereby protecting 2+ published by the Molkentin lab indicated that increased dystrophic muscle cells against Ca -dependent apopto- 2+ Ca entry by itself is sufficient to induce muscular dys- sis [108]. Hence, a concerted strategy to alleviate muscu- 2+ trophy in vivo, since transgenic mice overexpressing lar dystrophy likely requires the dampening of both Ca 2+ TRPC3 channels are characterized by features similar to influx as well as ER Ca release. the dystrophic disease models [75]. Finally, it is important to note that most of the evi- 2+ 2+ Different molecular mechanisms of increased Ca entry dence that points towards excessive Ca influx as an underpinning this disease model have been proposed, early event in the development of muscular dystrophy including store-operated and stretch-operated ion chan- has been obtained from mouse models. We need to nels [103]. On the one hand, TRPC channels seem impor- keep in mind that the need and physiological role of tant candidates [75]. Indeed, mdx dystrophic skeletal- SOCE might be different for mouse and human skeletal 2+ muscle fibers displayed increased TRPC-mediated Ca muscle. For instance, a micro-array analysis of human influx [73,75]. Interestingly, TRPC1 has been shown to skeletal-muscle biopsies from control patients and associate with the dystrophin-protein complex [104,105]. Duchenne muscular dystrophy patients (obtained from Moreover, dystrophic skeletal-muscle disease models asso- the Gene Expression Omnibus; http://www.ncbi.nlm.nih. ciated with mutations in the dystrophin or mutations in gov/geo/) indicated that the STIM1-mRNA levels were the delta-Sarcoglycan (Scgd) genes were rescued by trans- not increased, but rather tended to decrease in the mus- gene-mediated inhibition of TRPC channels, thereby redu- cle of the dystrophic patients, while Orai1-mRNA levels 2+ cing Ca influx and preventing the development of were not significantly changed (Figure 5). This seems in muscular-dystrophy features [75]. On the other hand, Lau- contrast with the up-regulation of STIM1 and Orai1 nikonis and co-workers demonstrated that while SOCE and the increased SOCE reported in mouse models for functions normally in mdx muscle fibers, the thresholds Duchenne muscular dystrophy. These contrasting find- for activation and deactivation of SOCE have been shifted ings may indicate that mechanisms underpinning SOCE 2+ to higher SR [Ca ] [106]. This may contribute to higher are differently affected in the human muscular patholo- 2+ Ca influx during long periods of stimulation. The gies versus the mouse models for these pathologies. In Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 11 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ Figure 5 Gene expression involved in Ca and/or contractility. Plots represent gene expression in quadriceps skeletal-muscle samples of controls (CTL, n = 10-12) and patients with Duchenne muscular dystrophy (DMD, n = 10 - 12) in arbitrary units (A.U.). Data were obtained from GEO reference series GSE1007 (STIM1, STIM2, ORAI1, ITPR1 and CASQ1) and GSE1004 (TRPC1, ATP2A1, RYR1 and MYH2) [116-118] comparing the mRNA-expression levels in normal and dystrophic patients (http://www.ncbi.nlm.nih.gov/geo/). Graphs represent box plots, indicating the mean th th th th (square symbol), the median (line), the 25 and 75 percentiles (bottom and top of the box), and the 5 and 95 percentiles (whisker range). Strikingly, STIM1-, SERCA1-, RyR1-mRNA levels tended to decline, while STIM2-, TRPC1- and IP R1-mRNA levels tended to increase. Orai1-, calsequestrin-1- and myosin heavy chain-2-mRNA levels did not significantly alter. This seems opposite to what has been observed in mouse 2+ models for Duchenne muscular dystrophy, which displayed excessive Ca influx and up-regulation of STIM1/Orai1 [106]. In human patients 2+ 2+ suffering from Duchenne muscular dystrophy, TRPC1 elevations may account for the increase in Ca influx, leading to Ca -dependent apoptosis and muscle degeneration. This indicates that caution should be taken from extrapolating results from mouse models for pathophysiological conditions to human pathophysiological conditions. Abbreviations indicate the gene names for stromal interaction molecule 1(STIM1), stromal interaction molecule 2 (STIM2), Orai1 (ORAI1), canonical transient receptor potential 1 (TRPC1), sarcoplasmic/endoplasmic- 2+ reticulum Ca -ATPase 1 (ATP2A1), ryanodine receptor 1 (RYR1), inositol 1,4,5-trisphosphate receptor 1 (ITPR1), calsequestrin 1 (CASQ1), and myosin heavy chain IIa (MYH2). addition, the relative importance of STIM1 versus human patients. In any case, it is clear that the role of STIM2 for SOCE in human muscles and their contribu- both STIM proteins for the development of myopathies tion to myopathies may differ among human and mice. in human patients must be further explored. In this respect, Duchenne muscular dystrophy patients Moreover, other mechanisms may account for the 2+ did show an up-regulation of STIM2-mRNA levels, excessive Ca influx that leads to muscle degeneration in 2+ which is activated at more modest decreases in [Ca ] human patients. Therefore, it is important to note that ER than STIM1. Therefore, STIM2 up-regulation may be TRPC1-mRNA levels are also significantly up-regulated in another critical factor that needs to be taken into the patients suffering from muscular dystrophy. Impor- account in the development of muscular dystrophy in tantly, excessive TRPC1 activity has been implicated in Kiviluoto et al. Skeletal Muscle 2011, 1:16 Page 12 of 15 http://www.skeletalmusclejournal.com/content/1/1/16 2+ 2+ Attraction Poles Program (Belgian Science Policy; P6/28 to HDS, JBP and LM). spontaneous Ca influx and the activation of Ca -depen- JPD is a Ph.D. fellow of the Agency for Innovation by Science and dent proteolysis, leading to the degradation of cytoskeletal Technology (IWT). The authors wish to thank Dr. Peter Vangheluwe for proteins and the development of myopathies in Homer providing materials. 1-deficient mice [111]. Decreased levels of Homer 1 in Authors’ contributions mdx mouse models may contribute to the reported GB conceived the experiments, analyzed the data and wrote the manuscript. TRPC1 hyperactivity in response to store depletion [73]. SK performed the experiments, analyzed the data and wrote the manuscript. JPD, HDS, LM and JBP discussed the data and revised the manuscript. However, the contribution of STIM1 in this process remains unknown. Competing interests Finally, these micro-array analyses also revealed that The authors declare that they have no competing interests. SERCA1- and RyR1-mRNA levels declined, IP R1- Received: 13 December 2010 Accepted: 4 April 2011 mRNA levels increased and Orai1-, calsequestrin-1- and Published: 4 April 2011 myosin heavy chain-2-mRNA levels did not significantly alter. Changes in IP R-expression level have previously 3 References 1. Putney JW Jr: A model for receptor-regulated calcium entry. 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Skeletal MuscleSpringer Journals

Published: Apr 4, 2011

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