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Muscle spindle function in healthy and diseased muscle

Muscle spindle function in healthy and diseased muscle Almost every muscle contains muscle spindles. These delicate sensory receptors inform the central nervous system (CNS) about changes in the length of individual muscles and the speed of stretching. With this information, the CNS computes the position and movement of our extremities in space, which is a requirement for motor control, for maintaining posture and for a stable gait. Many neuromuscular diseases affect muscle spindle function contributing, among others, to an unstable gait, frequent falls and ataxic behavior in the affected patients. Nevertheless, muscle spindles are usually ignored during examination and analysis of muscle function and when designing therapeutic strategies for neuromuscular diseases. This review summarizes the development and function of muscle spindles and the changes observed under pathological conditions, in particular in the various forms of muscular dystrophies. Keywords: Mechanotransduction, Sensory physiology, Proprioception, Neuromuscular diseases, Intrafusal fibers, Muscular dystrophy In its original sense, the term proprioception refers to development of head control and walking, an early im- sensory information arising in our own musculoskeletal pairment of fine motor skills, sensory ataxia with un- system itself [1–4]. Proprioceptive information informs steady gait, increased stride-to-stride variability in force us about the contractile state and movement of muscles, and step length, an inability to maintain balance with about muscle force, heaviness, stiffness, viscosity and ef- eyes closed (Romberg’s sign), a severely reduced ability fort and, thus, is required for any coordinated move- to identify the direction of joint movements, and an ab- ment, normal gait and for the maintenance of a stable sence of tendon reflexes [6–12]. The motor problems posture. Proprioception combines with other sensory are so severe that without the compensatory activity of systems to locate external objects relative to the body other senses, including the vestibular and the visual sys- and by this contributes to our body image and equili- tems, the patients are unable to maintain their posture, brioception. Since proprioception is vital for motor and walk or perform coordinated voluntary movements. In body control, patients with a loss of proprioception ei- addition, recent studies have uncovered exciting new ther due to an autoimmune disease [5] or due to a loss- functions for proprioception [4, 13]. For example, pro- of-function mutation in a protein essential for proprio- prioceptive information is required for the realignment ception [6] have prominent sensory and motor deficits, and proper healing of fractured bones [14] as well as for generally leading to ataxia and dysmetria. Patients with a the maintenance of spine alignment [15]. Thus, patients congenital absence of proprioception show delayed with proprioceptive deficits are likely to develop adoles- cent idiopathic scoliosis in their second decade of life, suggesting that the proprioceptive information may not * Correspondence: skroeger@lmu.de only provide dynamic control of spine alignment but Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Großhaderner Str. 9, 82152 also prevent progressive spinal deformation [13, 15]. Planegg-Martinsried, Germany © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 2 of 13 Moreover, after spinal cord injury, proprioceptive feed- unique sensory structures named palisade endings, back is essential for locomotor recovery and facilitates which might also provide proprioceptive information circuit reorganization [16]. Ablation of this feedback [23–25]. after behavioral recovery permanently reverts functional Muscle spindles are encapsulated sensory receptors improvements, demonstrating the essential role of pro- which inform the brain about changes in the length of prioception also for maintaining regained locomotor muscles [3, 20]. They consist of specialized muscle fibers function [17]. Thus, proprioceptive information has (so called intrafusal fibers) that are multiply innervated functions that extend far beyond motor control and in- and named according to the arrangement of their nuclei cludes non-conscious regulation of skeletal development as nuclear bag or nuclear chain fibers (a schematic rep- and function as well as recovery after spinal cord injury resentation of a muscle spindle is shown in Fig. 1a). [4, 18]. Intrafusal muscle fibers are up to 8-mm long in humans and about 400-μm long in mice and oriented parallel to Structure and function of muscle spindles the surrounding (extrafusal) muscle fibers. Each muscle Although Golgi tendon organs, joint receptors and other spindle contains on average 3–5 (mouse) [28]or8–20 sensory systems also contribute to proprioception, (human) [29] intrafusal fibers. With a diameter of 8 to muscle spindles are the most important proprioceptors 25 μm[30], intrafusal muscle fibers are much thinner [19, 20]. Muscle spindles are the most frequently found than extrafusal muscle fibers. Contractile filaments are sense organs in skeletal muscles and present in almost found in intrafusal fibers predominantly in the polar re- every muscle. The density of muscle spindles within the gions with only a small ring of sarcomeres underneath large muscle mass, however, is low so that they are ra- the sarcoplasmic membrane in the central (equatorial) ther difficult to detect. Rough estimates have suggested region (Fig. 1a). However, muscle spindles do not con- approximately 50,000 muscle spindles in the entire hu- tribute significantly to the force generated by the muscle man body [21]. Interestingly, in humans, muscle spindles [31, 32]. Nuclear bag fibers often extend beyond the are mostly absent in facial muscles [22] and extraocular fluid-filled fusiform capsule and are attached to intra- muscles have unusual muscle spindles and additional muscular connective tissue [33]. Nuclear chain fibers are Fig. 1 Structure of muscle spindles and distribution of the DGC. Panel a shows a schematic representation of the sensory and fusimotor innervation of intrafusal fibers. The connective tissue capsule is indicated in orange. Muscle spindles contain three types of intrafusal fibers: nuclear bag1, nuclear bag2, and nuclear chain fibers. Different parts of intrafusal fibers are innervated by different neurons: The central (equatorial) part is in intimate contact with afferent proprioceptive sensory neurons, termed primary “group Ia afferents” (forming the annulospiral endings) and (if present) secondary or “group II afferents”, marked in green and red, respectively. In addition to the sensory neurons, intrafusal muscle fibers are innervated by efferent γ-motoneurons (marked in black) in both polar regions, were they form a cholinergic synapse. The polar regions of intrafusal fibers contain most of the contractile elements (sarcomeres are indicated in blue in panel a). This schematic representation is based on the well-characterized muscle spindles from the cat’s tenuissimus muscle [19]. However, interspecies differences exist. For example, mouse muscle spindles might not have a group II innervation [26], and in humans, the sensory nerve terminal does not form annulospiral endings and the secondary ending innervates nuclear bag as well as nuclear chain muscle fibers [27]. Panel b shows a confocal section of the central part of a mouse muscle spindle stained with anti-neurofilament antibodies. Note the annulospiral endings of the Ia afferents in the central region. The γ-motoneuron endplates are located outside the picture Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 3 of 13 attached to the polar regions of the thicker and longer [39]. When present, the smaller group II fiber terminals nuclear bag fibers [33]. flank the primary annulospiral endings in the equatorial Functionally, muscle spindles are stretch detectors, i.e. region (Fig. 1a). There may be several group II fibers in- they sense how much and how fast a muscle is length- nervating each human spindle [40]. The cell bodies of ened or shortened [19]. Accordingly, when a muscle is these proprioceptive afferent fibers constitute 5–10% of stretched, this change in length is transmitted to the all neurons in the dorsal root ganglion [36]. They can be spindles and their intrafusal fibers which are subse- classified and distinguished from other dorsal root gan- quently similarly stretched. To respond appropriately to glion neurons as a unique neuronal population using changes in muscle fiber length, intrafusal fibers are in- single cell transcriptome analysis [36, 41, 42]. nervated by two kinds of neurons: afferent sensory neu- Afferent sensory neurons generate action potentials rons and efferent motoneurons (Fig. 1a). In humans, the with frequencies that correspond to the size of the sensory innervation of the muscle spindle arises from stretch and to the rate of stretching [43] (Fig. 2). Sensory both group Ia and group II afferent fibers (also some- neurons innervating bag1 fibers respond maximally to times called type Ia or type II fibers, respectively), which the velocity of changes in muscle fiber length (dynamic differ in their axonal conduction velocity [34]. In con- sensitivity) and those innervating bag2 fibers as well as trast, in mice an innervation by group II fibers has so far nuclear chain fibers respond maximally to the amount of not been detected by histological or functional assays stretch (static sensitivity). For a recent review on the [26, 35]. However, transcriptome analysis of DRG pro- mechanotransduction processes within the sensory nerve prioceptive neurons has recently suggested the existence terminal, see [45]. of group II fibers also in mice [36]. There is usually only Sensory neuron activity from muscle spindles can be a single Ia afferent fiber per spindle, and every intrafusal electrophysiologically recorded and characterized in a muscle fiber within that spindle receives innervation number of different ways. In humans, for example, indi- from that sensory neuron. In cat, rat and mice (and vidual sensory afferent (“single unit”) action potentials probably many other species), the axon terminals of this can be studied in vivo by intraneural microelectrodes sensory afferent fiber coil around the central (equatorial) inserted into accessible peripheral nerves (microneuro- part of both nuclear bag and nuclear chain fibers, form- graphy), such as the median and ulnar nerves at the ing the primary endings (also called annulospiral end- wrist or upper arm, the radial nerve in the upper arm, ings) [37, 38] (Fig. 1b). In humans, sensory terminals and the tibial and common peroneal nerves in the lower form irregular coils with branches and varicose swellings limb [29]. In mice, single unit muscle spindle afferent Fig. 2 Typical responses of a muscle spindle to stretch. The responses of an individual muscle spindle from the mouse extensor digitorum longus muscle to ramp and hold stretches applied to the tendon were recorded with an extracellular electrode. Single unit action potentials are shown in (a and d). The stretch was 4-s long, and the length change corresponded to 260 (panel b) and 780 (panel e) μm. The ramp speed in (e) was 3- fold higher compared to that in (b). Panels c and f represent the instantaneous frequencies (action potentials/s). In panel f, three different parameters that are usually analyzed to describe muscle spindle function are illustrated: resting discharge (RD), dynamic peak (DP), and static response (SR). For more information on these parameters, see [32, 33, 44]. Note that the dynamic peak and the static response is higher in (f), compared in (c) due to the higher ramp speed and the longer length change. Since the fusimotor innervation was cut during the dissection of the muscle, no action potentials can be observed directly after the end of the ramp and hold stretch (spindle pause) Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 4 of 13 responses to ramp-and-hold stretches and sinusoidal vi- muscle spindles can be recognized in fetal tissue around bratory stimuli have been well characterized in an the 11th week of gestation [52, 53], but little is known ex vivo adult mouse extensor digitorum longus prepar- about the molecular basis of human muscle spindle de- ation dissected with the innervating nerve attached [26, velopment. In contrast, muscle spindle development is 46]. A typical example for a single unit muscle spindle much better characterized in rodents, where muscle response to two different ramp-and-hold stretches in the spindle differentiation begins around embryonic day 14 adult mouse extensor digitorum longus muscle is shown when the growth cone of the sensory neuron’s axon in Fig. 2. In many species, muscle spindles exhibit a rest- reaches its target muscle. Fusimotor innervation de- ing discharge that is related to the degree of muscle velops a few days later and is present in mice at E19 stretch but the frequency of the mean firing rate differs [54]. In rodents and humans, immature myotubes are in- between species. In mice at room temperature, the fre- duced to differentiate into intrafusal fibers when sensory quency is ~ 15 Hz (Fig. 2). Muscle spindle afferents en- afferent axons contact the primary myotubes [55–57]. code muscle length in their frequency of firing, i.e. the Apparently, nuclear bag fibers differentiate before nu- more the muscle is stretched, the higher the frequency clear chain fibers in rats [58, 59]. There is the possibility (static response). In addition to the static encoding of of a hyperinnervation of intrafusal fibers with subse- length changes, spindle afferents, especially primary af- quent pruning of the terminals for the fusimotor innerv- ferents, can respond to dynamic length changes, i.e. the ation [60] as well as for the sensory innervation [61]of faster the stretch, the higher the frequency during the rat muscle spindles. In mice, the intrafusal fibers are ini- ramp phase. Accordingly, the instantaneous frequency tially surrounded by a “web-like” network of sensory (action potentials/s) shown in Fig. 2 is higher the faster axons, which is reduced to an adult primary ending from the stretch is and the longer the length change is. a single sensory neuron (Fig. 3). Human muscle spindles In addition to sensory neurons, intrafusal muscle fibers are functional at birth, but their response to stretch is are also innervated by efferent motoneurons (fusimotor immature [30]. Moreover, with the postnatal increase in innervation; Fig. 1a) [47]. Both β- and γ-motoneurons muscle mass and mobility, sensory nerve terminals in innervate intrafusal fibers, but γ-motoneurons are con- mice and humans undergo a number of anatomical and siderably more abundant and much better characterized physiological changes [62–64]. By postnatal day 18, compared to β-motoneurons [48]. Gamma-motoneurons muscle spindle afferent firing is indistinguishable from constitute about 30% of all motoneurons in the ventral the firing in adult rats suggesting that muscle spindle horn of the spinal cord. Axons of motoneurons usually maturation continues into postnatal life and that muscle enter the spindle together with the sensory fibers in the spindles are capable of responding to stretch, even at an central region but innervate intrafusal muscle fibers ex- age when their morphological and ultrastructural matur- clusively in the polar regions. The endplates of γ- ation is not yet fully accomplished [65]. motoneurons differ structurally from the neuromuscular After the establishment of a physical contact between junctions formed by α-motoneurons on extrafusal fibers, the sensory axon and the primary myotube, both cells but both are cholinergic synapses with many features in exchange inductive signals ensuring the differentiation common, including junctional folds and a basal lamina of intrafusal fiber and the survival of the sensory neuron. filling the synaptic cleft [47]. Moreover, both synapses This reciprocal signaling is essential for muscle spindle require the extracellular matrix synapse organizer agrin differentiation and intrafusal fiber development. Accord- and its receptor complex (consisting of the low-density ingly, elimination of the sensory input (but not of the lipoprotein receptor-like protein 4 and the tyrosine kin- fusimotor input) in embryonic and adult muscle spindles ase MuSK) for their formation, suggesting a common results in a rapid degeneration of the intrafusal fibers molecular basis for their synaptogenesis [49]. Gamma- ([66–68]; for review, see [55]). The key inductive factor motoneurons induce contractions of sarcomeres in the for the sensory neuron-mediated muscle spindle differ- polar region to exert tension on the central region of entiation is the immunoglobulin form of neuregulin-1 intrafusal fibers [47, 50]. This prevents the slackening of (Ig-Nrg1). Ig-Nrg1 is expressed by proprioceptive neu- intrafusal fibers during muscle shortenings and allows rons [69, 70], and its release from sensory neurons and for continuous adjustment of the mechanical sensitivity subsequent binding to the ErbB2 receptor expressed by of spindles over the wide range of muscle lengths and immature muscle fibers [71] induces their differentiation stretch velocities that occur during normal motor into intrafusal muscle fibers. Accordingly, Nrg1- or behaviors. ErbB2-deficient mice do not initiate muscle spindle dif- ferentiation, do not elaborate Ia afferent terminals and Muscle spindle development and ageing have an ataxic behavior as well as abnormal hind limb Muscle spindle development starts during embryonic reflexes, consistent with severe proprioceptive deficits stages but continues well into adult life [51]. Human [69–72]. Nrg1–ErbB2 signaling activates downstream Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 5 of 13 Fig. 3 Postnatal development of mouse muscle spindles. Muscle spindles from postnatal day 0: P0 (a), P8 (b), and P40 (c). Thy1-YFP mouse extensor digitorum longus were stained with anti-GFP antibodies. Only the central (equatorial) region is shown. Note the transformation of the “web-like” appearance of the sensory nerve terminal into the typical annulospiral ending during postnatal development. Scale bar in all panels: 50 μm targets such as the transcription factor early growth re- On the other hand, muscle fibers release sponse protein 3 (Egr3)[73–75], and the Ets transcrip- neurotrophin-3 (NT3), which activates the tropomyosin tion factors Pea3, Erm and Er81 as well as the Grb2- receptor kinase C (TrkC) receptor on proprioceptive associated binder 1 protein, a scaffolding mediator of re- sensory neurons and by this secures the survival of the ceptor tyrosine kinase signaling [69, 76, 77]. Although sensory neuron [79–81]. The TrkC/NT3 signaling sys- muscle spindles are initially generated in Egr3-deficient tem is, however, not required for the initiation of muscle mice [75], subsequently most of them degenerate, result- spindle differentiation [82]. Muscle-specific overexpres- ing in ataxic behavior [73, 74]. Overexpression of Egr3 in sion of NT3 results in an increase in the number of pro- primary myotubes on the other hand leads to their dif- prioceptive afferents and muscle spindles [83–85]. NT3/ ferentiation into intrafusal fibers [78], suggesting that TrkC signaling induces the expression of the Etv1 (Er81) this transcription factor is necessary and sufficient for transcription factor in proprioceptive sensory neurons muscle spindle maintenance. Interestingly, Ig-Nrg1 is [76, 86]. Interestingly, the survival of proprioceptive sen- the substrate for the membrane-bound aspartyl protease sory neurons supplying distinct skeletal muscles differ in Bace1 (also called β-secretase 1). Cleavage of Ig-Nrg1 is their dependence on Etv1 for their survival and differen- required for Ig-Nrg1 function and, accordingly, in the tiation [87]. The survival and/or specification of the absence of Bace1, muscle spindle numbers are reduced TrkC-positive proprioceptive afferents also requires the and spindle maturation is impaired. Moreover, a graded expression of the Runt-related transcription factor 3 reduction in Ig-Nrg1 signal strength in vivo induced by (Runx3) and Runx3-knockout mice display severe limb pharmacological Bace1 inhibition results in increasingly ataxia due to absence of proprioceptive sensory neurons severe deficits in the formation and maturation of [88, 89]. muscle spindles in combination with a reduced motor As in the musculoskeletal system in general, various coordination [70]. The continuous presence of Bace1 elements of the proprioceptive system decline during and Ig-Nrg1 is essential to maintain muscle spindles in ageing [90, 91]. These changes might contribute to the adult muscle, since either pharmacological inhibition of frequent falls and motor control problems observed in Bace1 or induced Bace1 deficiency in adult propriocep- older adults. On the structural level, muscle spindles in tive neurons also leads to a decline of muscle spindle aged humans possess fewer intrafusal fibers, an increased number [70]. In summary, the sensory neuron induces capsular thickness and some spindles which show signs the differentiation of muscle spindles from immature of denervation [92, 93]. In old rats, primary endings are myotubes via Ig-Nrg1, Bace1 and ErbB2-mediated acti- less spiral or non-spiral in appearance, but secondary vation of Egr3. endings appeared unchanged [94, 95]. Likewise, in old Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 6 of 13 mice, there is a significant increase in the number of Ia the dystrophin/DGC-mediated molecular connection afferents with large swellings that fail to properly wrap lead to mechanical lability of the sarcolemmal mem- around intrafusal muscle fibers. There is also a degener- brane and subsequent contraction-induced damage [114, ation of proprioceptive sensory neuron cell bodies in the 120–122]. While regeneration of damaged muscle fibers dorsal root ganglion but no change in the morphology occurs initially, it cannot compensate for the prolonged and number of intrafusal muscle fibers [96]. In addition, degenerative loss of muscle tissue [123], leading over electrophysiological studies showed that mature rat time to a reduction of muscle mass, loss of contractile muscle spindles display a lower dynamic response of pri- force and, in the case of DMD, to premature death of mary endings compared with those of young animals the affected person due to respiratory or cardiac muscle [94]. Taken together, the proprioceptive system under- failure [124]. goes significant structural and functional changes with Many muscular dystrophy patients suffer from postural advancing age and the changes are consistent with a instability, sudden spontaneous falls and poor manual gradual decline in proprioceptive function in elderly in- dexterity [125–128], suggesting that their proprioceptive dividuals and animals. system might be impaired. However, only minor morpho- logical changes in muscle spindles were detected in hu- Muscle spindle structure and function in muscular man dystrophic muscles. These changes primarily affect dystrophy the connective tissue surrounding intrafusal fibers. For ex- An impaired proprioception, in some cases associated ample, thickening of the capsule and of the connective tis- with an altered muscle spindle morphology, has been sue septa inside the spindle and an “oedematous swelling” documented as a secondary effect in many diseases. of the spindle were reported in muscle biopsy specimens These include Parkinson’s disease [97], Huntington’s dis- from Duchenne- and limb-girdle muscular dystrophy pa- ease [98], multiple sclerosis [99], Charcot-Marie-Tooth tients [106]. Likewise, analyses of biopsy specimens from type 2E [100], traumatic or neurotoxic injury [101], patients with muscular dystrophy and with congenital dys- spinal muscular atrophy [102], diabetic neuropathy [103, trophy revealed an increased thickness of the spindle cap- 104] and myasthenia gravis [105, 106]. In amyotrophic sule and a slight decrease of the intrafusal fiber diameter lateral sclerosis, sensory neurons are similarly affected as [129]. An autopsy study of seven DMD patients aged 15 α-motoneurons [107–110]. They accumulate misfolded to 17 years reported more severe pathological changes in- SOD1 protein and the annulospiral endings degenerate, cluding degenerative changes, atrophy and loss of intrafu- leading to ataxia and motor control problems [107, 109]. sal muscle fibers [130], but it is unclear if these more In contrast to α-motoneurons, γ-motoneurons appar- extensive changes were caused by the disease or due to ently survive degeneration in murine models of amyo- postmortem tissue degeneration. This possibility has to be trophic lateral sclerosis and spinal muscular atrophy considered, since proprioceptive functions of muscle spin- [111–113], suggesting differential vulnerabilities for both dles in DMD patients appear rather normal (see below) types of motoneurons in both diseases. and since a recent study analyzing muscle spindles from a Recently, a number of studies have analyzed proprio- 27-year-old severely affected DMD patient described that ception and muscle spindle function in patients with spindle size and number as well as the size of intrafusal muscular dystrophy and in dystrophic mouse models. myofibers and capsule thickness were in the normal range Muscular dystrophies are a heterogeneous group of [131]. Interestingly, the extrafusal fibers directly surround- more than 30 different mostly inherited diseases charac- ing the muscle spindles were also less affected by the de- terized by muscular weakness and atrophy in combin- generative events compared to fibers further away from ation with degeneration of the musculoskeletal system the spindle, suggesting the possibility of a more protective [114]. The molecular basis of many muscular dystro- environment directly around muscle spindles. phies are mutations that directly or indirectly influence Likewise, murine models for several muscular dystro- the function of the dystrophin-associated glycoprotein phies display only minor changes in muscle spindle complex (DGC) [115, 116]. The most common form of structure compared to wildtype control mice. For ex- muscle dystrophy in humans is Duchenne muscular dys- ample, muscle spindles in the soleus muscle from 1- dy-2J/dy-2J dy2J/dy2J trophy (DMD) which affects approximately 1 in 5000 year-old C57BL/6J (Lama2 ) dystrophic boys [117]. DMD is caused by mutations in the DMD mice, a model for laminin α2 (merosin)-deficient con- gene, which codes for the large cytoskeletal protein dys- genital muscular dystrophy, had a small but significant trophin [114]. In skeletal muscle, dystrophin links sub- increase in the diameter of the outer capsule and in the sarcolemmal F-actin filaments to the extracellular matrix overall thickness of the equatorial region [132]. But, as via the DGC [118, 119]. This link mechanically stabilizes in the corresponding patients, intrafusal fibers and sen- the sarcolemmal membrane particularly during muscle sory terminals appeared mostly spared from degener- mdx contraction. Mutations which cause an interruption of ation [44, 132]. Similarly, the DMD mouse line [133], Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 7 of 13 a widely used model system for muscular dystrophy of remains present at the neuromuscular junction, the the Duchenne type [134], revealed no reduction of the myotendinous junction and blood vessels [143–146]. In mdx total number of muscle spindles and no change in the extrafusal muscle fibers from DMD mice, utrophin is structure of muscle spindles and their sensory innerv- greatly upregulated and present along the entire sarco- ation [135, 136]. Thus, compared to extrafusal muscle fi- lemma [147, 148]. The upregulation of utrophin expres- bers, the morphology of intrafusal muscle fibers and of sion in extrafusal muscle fibers can lessen or even mdx muscle spindles generally appear much less affected by prevent the dystrophic phenotype in DMD mice and the degenerative processes in humans and in mice with muscular dystrophy patients [149–153]. The upregula- mdx Duchenne-type muscular dystrophy. tion of utrophin in intrafusal fibers of DMD mice The mechanism(s), which protect intrafusal myofibers might therefore functionally compensate for the absence from degeneration and wasting, are unknown. Capsular of dystrophin and prevent the degeneration of intrafusal thickening in the equatorial region may be an adaptive re- fibers. However, intrafusal muscle fibers from DMD pa- sponse, preventing the intrafusal fibers from undergoing tients are utrophin-negative [131], suggesting that the atrophy. Another explanation for the sparing of muscle upregulation of this protein cannot solely explain the spindles in DMD patients could be a better maintenance preservation of intrafusal muscle fibers in humans. of the intracellular calcium homeostasis similar to what An obvious question arising from these observations is has been described for extraocular muscles [137]. Further- whether the relatively minor structural changes in more, the mild phenotypic effect of the dystrophin muta- muscle spindles from DMD patients and corresponding tions might be due to the different surface-to-volume mouse models are accompanied by functional changes. ratio, compared to extrafusal fibers. Intrafusal fibers are Analysis of single unit sensory afferent recordings from mdx thinner compared to extrafusal fibers, have a much DMD mice showed that muscle spindles have a nor- smaller mechanical burden, and generate considerably less mal response to ramp-and-hold stretches and only a contractile force. They are therefore less likely to suffer slightly increased response to sinusoidal vibrations [136]. from mechanical damage [138]. More strikingly, the resting discharge, i.e. the action po- Immunohistochemical analysis showed that dystrophin tential frequency of sensory afferents from a resting is present in the sarcolemma of the polar regions of muscle spindle (Fig. 2), was significantly increased in mdx intrafusal fibers [139]. In contrast, in the equatorial re- DMD mice compared to control mice. This increase gion, dystrophin is absent from that part of the intrafusal in the resting discharge might be clinically relevant since fiber, which is in contact with the sensory nerve terminal it would cause an increased muscle tone via the muscle but concentrated in parts without sensory nerve contact stretch reflex, which would lead to an increase in muscle [136, 139] (Fig. 4a–d). Other proteins of the DGC (in- stiffness and an aggravation of the degenerative events in cluding alpha-dystrobrevin1; Fig. 4k) have a similar dis- extrafusal fibers of DMD patients. tribution. The area, where the DGC is concentrated, also Interestingly, a similar increase of the resting discharge −/− corresponds to the region where the intrafusal fiber has was observed in SJL-Dysf C57BL/6 (dysf ) mice [136], direct contact to the basal lamina. The interaction of a murine model system for dysferlinopathies [154, 155]. DGC components with basal lamina proteins might Dysferlinopathies (including limb girdle muscular dys- stabilize and help to maintain the subcellular concentra- trophy 2B and Miyoshi myopathy) are muscular dystro- tion of the DGC in this region of the intrafusal fiber. In phies characterized by muscle weakness and wasting but any case, the unusual distribution of DGC components differ from DMD in the molecular etiology and disease indicates a molecular specialization in particular regions progression [156]. They are caused by mutations in the of the intrafusal fiber plasma membrane. DYSF gene that impair the function of dysferlin [157– As expected, dystrophin is absent in intrafusal fibers of 159], a single pass transmembrane protein with import- mdx DMD mice [136] (Fig. 4e–g). However, utrophin ex- ant roles in membrane fusion and trafficking [156, 160, pression is markedly upregulated and has a similar dis- 161]. When microlesions in the plasma membrane mdx tribution in DMD mice as dystrophin in wildtype occur, vesicles are recruited to the injury site and dysfer- mice [136] (Fig. 1e–j). Utrophin is an autosomally lin then appears to participate in the resealing of the in- encoded paralogue of dystrophin [136]. It shares more jury site by promoting vesicle aggregation and fusion than 80% amino acid sequence similarity to dystrophin, with the plasma membrane [162, 163]. Accordingly, loss has a similar domain structure and like dystrophin can of dysferlin leads to an impaired membrane repair and interact with actin filaments and with DGC components degeneration of skeletal muscle fibers, causing the [140]. In skeletal muscle, utrophin is highly expressed in muscle weakness. Additional functions of dysferlin, in- 2+ fetal and regenerating muscle fibers [141, 142]. In adult cluding an impaired Ca homeostasis during mechan- wildtype muscle fibers, utrophin is replaced by dys- ical stress [164], might contribute to the degeneration of mdx trophin along the entire sarcolemmal membrane but skeletal muscle. Like in the DMD mouse, muscle Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 8 of 13 Fig. 4 Distribution of the dystrophin glycoprotein complex in mouse intrafusal fibers. Panel a shows two intrafusal fibers labeled by anti- dystrophin antibodies (red channel) and by antibodies against the vesicular glutamate transporter 1 (vGluT1; white channel). Panels b–d show the boxed area in panel c at a higher magnification. Note that dystrophin is concentrated in the intrafusal fiber plasma membrane in areas that are not in contact with the sensory neuron. The blue color represents nuclei stained with 4′,6-diamidin-2-phenylindol (DAPI). Panels e–j show the mdx distribution of utrophin (red channel) in the central region of muscle spindles from wildtype (e–g) and from DMD mice (h–j). Anti-vGluT1 antibodies (green channel in panels e–j) were used to label the sensory nerve terminal. Panels d, g and j show the merged channels. Utrophin is mdx not detectable in the equatorial region of muscle fibers from wildtype mice (e) but severely upregulated in intrafusal fibers from DMD mice (h). Note the absence of utrophin in the contact area between intrafusal fiber and sensory nerve terminal. Asterisks mark corresponding positions in all panels. Panel k shows a single confocal section of a muscle spindle stained with antibodies against vGluT1 (magenta) and against dystrobrevin (green) to indicate that other components of the DGC have a similar distribution as dystrophin, i.e. are concentrated in areas of the intrafusal fiber that are not in contact with the sensory nerve terminal spindle number and morphology of intrafusal fibers and patients perceive passive movements, experience illusory their innervation were not changed, but the resting dis- movement induced by muscle tendon vibration, and charge frequency was increased qualitatively and quantita- have proprioceptive-regulated sways in response to vi- mdx tively similar to DMD mice [136]. The similarity of the bratory stimulation applied to the neck and ankle muscle mdx −/− functional changes in DMD and dysf mice suggests tendons [165]. Moreover, reinforcement maneuvers in- a common deficit in both mouse strains, but the molecu- creased the sensitivity of muscle spindle afferents to im- lar mechanism is unknown. The double-mutant mice did posed movements of the ankle in a similar way in DMD not have an aggravated phenotype, suggesting that both patients and in non-affected controls [166]. These find- mutations coalesce on the same pathway [136]. ings argue for either preserved proprioceptive functions In contrast to the functional changes in murine model of muscle spindles or the activation of compensatory systems for different forms of muscular dystrophy, little mechanisms. if any functional deficits have been observed in muscular The morphological phenotype in Duchenne muscular dystrophy patients. For example, muscular dystrophy dystrophy is rather mild, but are considerably more Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 9 of 13 severe in muscle spindles from patients with myotonic been successfully used during rehabilitation to reduce dystrophy, where extensive intrafusal fiber splitting was the decline of motor control in subjects with facioscapu- reported [167, 168]. In addition, sensory endings were lohumeral muscular dystrophy [180] and with Parkinson undetectable on nuclear bag and nuclear chain fibers. In patients [181]. In muscular dystrophy patients, this train- agreement with these pronounced ultrastructural ing slows down the deleterious effects of the gradual de- changes, areflexia has been reported in myotonic dys- cline of motor abilities [166]. Since muscle spindle trophy [169], congenital dystrophies [170] and centro- afferent firing is modified by the emotional context nuclear myopathy [171], but not in patients with tibial [182], it is conceivable to exploit the emotional situation muscular dystrophy [172]. and vibrational stimuli during physical rehabilitation or In summary, studies in humans and mice with muscu- training to increase proprioceptive acuity. lar dystrophies show various degrees of impairment of Finally, muscle spindle preservation in DMD may be muscle spindle function and proprioception. The deficits an important factor to exploit new therapeutic ap- could alter joint coordination, impair movements and proaches for muscular dystrophy patients. For example, contribute to the instable gait, frequent falls and motor the strong upregulation of the utrophin expression in mdx control problems of muscular dystrophy patients. Care- intrafusal fibers from DMD mice [136] might be used givers and patients should therefore consider an im- to investigate the regulation of the utrophin expression paired proprioception when developing guidelines and in more detail. Since utrophin can functionally compen- when testing new interventions. sate dystrophin deficiency, a better understanding of the signaling cascade underlying utrophin upregulation in mdx Therapeutic strategies to improve muscle spindle DMD mice might aid in developing strategies for a function and proprioception pharmacological or genetic activation of utrophin ex- The most prevalent symptom of all muscular dystrophy pression [183], which might also be applicable to upreg- patients is the loss and wasting of skeletal muscle tissue. ulate utrophin expression in extrafusal fibers. Therefore, common therapeutic interventions for pa- In summary, therapeutic strategies for muscular dys- tients with muscular dystrophy must aim at increasing trophy patients should include in addition to strengthen- muscle strength and reducing muscle fatigue and degen- ing the contractile muscle force, the preservation of eration. A proprioceptive impairment is certainly not the muscle spindles and the sensitization of proprioception sole cause for the motor control problems in these pa- in order to maintain appropriate motor control and a tients, but the important role of the sensory system con- stable gait and posture. trolling motor coordination should not be ignored. In Abbreviations any neuromuscular disease, therapeutic strategies should CNS: Central nervous system; DAPI: 4′,6-Diamidin-2-phenylindol; DGC: Dorsal therefore also aim at restoring/maintaining propriocep- root ganglion; DMD: Duchenne muscular dystrophy; DP: Dynamic peak; ErbB2: Erb-b2 receptor tyrosine kinase 2; Egr3: Early growth response protein tion and muscle spindle function. 3; Etv1: ETS variant transcription factor 1; Ig-Nrg1: Immunoglobulin form of Several ways of improving muscle spindle function in neuregulin-1; MuSK: Muscle-specific kinase; NT3: Neurotrophin-3; P: Postnatal dystrophic patients can be envisioned. The recent identi- day; RD: Resting discharge; Runx3: Runt-related transcription factor 3; SR: Static response; TrkC receptor: Tropomyosin receptor kinase C receptor; fication of the Piezo2 channel as the primary mechano- vGluT1: Vesicular glutamate transporter 1 transduction channel [6, 173] might be exploited to develop drugs, which specifically target mechanosensitiv- Acknowledgements The author would like to thank Edith Ribot-Ciscar, Benedikt Schoser, Bob ity without interfering with extrafusal muscle fiber func- Banks and Guy Bewick for critically reading and improving the manuscript. tion or with neuromuscular transmission [174]. These The contribution of Sarah Rossmanith and Yina Zhang to Figs. 3 and 4 is drugs could either directly affect the Piezo2 channel gratefully acknowledged. [175] or indirectly, for example via modulatory Gi- Authors’ contributions coupled receptors [176]. However, potential drugs still All authors participated in the design and coordination of the text and await clinical trials and approval and side effects due to helped to draft this review. All authors prepared, read and approved the final manuscript. interference with Piezo2 channels in non-muscle tissues might limit their application [174]. Funding Alternatively, training of the proprioceptive sense is a Research in the lab of the first author is supported by the German Research Foundation (DFG; Kr1039/16), the Friedrich-Baur-Society, the German Society valuable behavioral therapy for improving impaired for Muscle Disease (DGM), the German Academic Exchange Service (DAAD), motor function and can significantly improve motor and the Munich Center for Neurosciences—Brain & Mind. control dysfunctions in many neuromuscular disorders Availability of data and materials and in aging-related proprioceptive decline [177]. 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Muscle spindle function in healthy and diseased muscle

Skeletal Muscle , Volume 11 (1) – Jan 7, 2021

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Abstract

Almost every muscle contains muscle spindles. These delicate sensory receptors inform the central nervous system (CNS) about changes in the length of individual muscles and the speed of stretching. With this information, the CNS computes the position and movement of our extremities in space, which is a requirement for motor control, for maintaining posture and for a stable gait. Many neuromuscular diseases affect muscle spindle function contributing, among others, to an unstable gait, frequent falls and ataxic behavior in the affected patients. Nevertheless, muscle spindles are usually ignored during examination and analysis of muscle function and when designing therapeutic strategies for neuromuscular diseases. This review summarizes the development and function of muscle spindles and the changes observed under pathological conditions, in particular in the various forms of muscular dystrophies. Keywords: Mechanotransduction, Sensory physiology, Proprioception, Neuromuscular diseases, Intrafusal fibers, Muscular dystrophy In its original sense, the term proprioception refers to development of head control and walking, an early im- sensory information arising in our own musculoskeletal pairment of fine motor skills, sensory ataxia with un- system itself [1–4]. Proprioceptive information informs steady gait, increased stride-to-stride variability in force us about the contractile state and movement of muscles, and step length, an inability to maintain balance with about muscle force, heaviness, stiffness, viscosity and ef- eyes closed (Romberg’s sign), a severely reduced ability fort and, thus, is required for any coordinated move- to identify the direction of joint movements, and an ab- ment, normal gait and for the maintenance of a stable sence of tendon reflexes [6–12]. The motor problems posture. Proprioception combines with other sensory are so severe that without the compensatory activity of systems to locate external objects relative to the body other senses, including the vestibular and the visual sys- and by this contributes to our body image and equili- tems, the patients are unable to maintain their posture, brioception. Since proprioception is vital for motor and walk or perform coordinated voluntary movements. In body control, patients with a loss of proprioception ei- addition, recent studies have uncovered exciting new ther due to an autoimmune disease [5] or due to a loss- functions for proprioception [4, 13]. For example, pro- of-function mutation in a protein essential for proprio- prioceptive information is required for the realignment ception [6] have prominent sensory and motor deficits, and proper healing of fractured bones [14] as well as for generally leading to ataxia and dysmetria. Patients with a the maintenance of spine alignment [15]. Thus, patients congenital absence of proprioception show delayed with proprioceptive deficits are likely to develop adoles- cent idiopathic scoliosis in their second decade of life, suggesting that the proprioceptive information may not * Correspondence: skroeger@lmu.de only provide dynamic control of spine alignment but Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Großhaderner Str. 9, 82152 also prevent progressive spinal deformation [13, 15]. Planegg-Martinsried, Germany © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 2 of 13 Moreover, after spinal cord injury, proprioceptive feed- unique sensory structures named palisade endings, back is essential for locomotor recovery and facilitates which might also provide proprioceptive information circuit reorganization [16]. Ablation of this feedback [23–25]. after behavioral recovery permanently reverts functional Muscle spindles are encapsulated sensory receptors improvements, demonstrating the essential role of pro- which inform the brain about changes in the length of prioception also for maintaining regained locomotor muscles [3, 20]. They consist of specialized muscle fibers function [17]. Thus, proprioceptive information has (so called intrafusal fibers) that are multiply innervated functions that extend far beyond motor control and in- and named according to the arrangement of their nuclei cludes non-conscious regulation of skeletal development as nuclear bag or nuclear chain fibers (a schematic rep- and function as well as recovery after spinal cord injury resentation of a muscle spindle is shown in Fig. 1a). [4, 18]. Intrafusal muscle fibers are up to 8-mm long in humans and about 400-μm long in mice and oriented parallel to Structure and function of muscle spindles the surrounding (extrafusal) muscle fibers. Each muscle Although Golgi tendon organs, joint receptors and other spindle contains on average 3–5 (mouse) [28]or8–20 sensory systems also contribute to proprioception, (human) [29] intrafusal fibers. With a diameter of 8 to muscle spindles are the most important proprioceptors 25 μm[30], intrafusal muscle fibers are much thinner [19, 20]. Muscle spindles are the most frequently found than extrafusal muscle fibers. Contractile filaments are sense organs in skeletal muscles and present in almost found in intrafusal fibers predominantly in the polar re- every muscle. The density of muscle spindles within the gions with only a small ring of sarcomeres underneath large muscle mass, however, is low so that they are ra- the sarcoplasmic membrane in the central (equatorial) ther difficult to detect. Rough estimates have suggested region (Fig. 1a). However, muscle spindles do not con- approximately 50,000 muscle spindles in the entire hu- tribute significantly to the force generated by the muscle man body [21]. Interestingly, in humans, muscle spindles [31, 32]. Nuclear bag fibers often extend beyond the are mostly absent in facial muscles [22] and extraocular fluid-filled fusiform capsule and are attached to intra- muscles have unusual muscle spindles and additional muscular connective tissue [33]. Nuclear chain fibers are Fig. 1 Structure of muscle spindles and distribution of the DGC. Panel a shows a schematic representation of the sensory and fusimotor innervation of intrafusal fibers. The connective tissue capsule is indicated in orange. Muscle spindles contain three types of intrafusal fibers: nuclear bag1, nuclear bag2, and nuclear chain fibers. Different parts of intrafusal fibers are innervated by different neurons: The central (equatorial) part is in intimate contact with afferent proprioceptive sensory neurons, termed primary “group Ia afferents” (forming the annulospiral endings) and (if present) secondary or “group II afferents”, marked in green and red, respectively. In addition to the sensory neurons, intrafusal muscle fibers are innervated by efferent γ-motoneurons (marked in black) in both polar regions, were they form a cholinergic synapse. The polar regions of intrafusal fibers contain most of the contractile elements (sarcomeres are indicated in blue in panel a). This schematic representation is based on the well-characterized muscle spindles from the cat’s tenuissimus muscle [19]. However, interspecies differences exist. For example, mouse muscle spindles might not have a group II innervation [26], and in humans, the sensory nerve terminal does not form annulospiral endings and the secondary ending innervates nuclear bag as well as nuclear chain muscle fibers [27]. Panel b shows a confocal section of the central part of a mouse muscle spindle stained with anti-neurofilament antibodies. Note the annulospiral endings of the Ia afferents in the central region. The γ-motoneuron endplates are located outside the picture Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 3 of 13 attached to the polar regions of the thicker and longer [39]. When present, the smaller group II fiber terminals nuclear bag fibers [33]. flank the primary annulospiral endings in the equatorial Functionally, muscle spindles are stretch detectors, i.e. region (Fig. 1a). There may be several group II fibers in- they sense how much and how fast a muscle is length- nervating each human spindle [40]. The cell bodies of ened or shortened [19]. Accordingly, when a muscle is these proprioceptive afferent fibers constitute 5–10% of stretched, this change in length is transmitted to the all neurons in the dorsal root ganglion [36]. They can be spindles and their intrafusal fibers which are subse- classified and distinguished from other dorsal root gan- quently similarly stretched. To respond appropriately to glion neurons as a unique neuronal population using changes in muscle fiber length, intrafusal fibers are in- single cell transcriptome analysis [36, 41, 42]. nervated by two kinds of neurons: afferent sensory neu- Afferent sensory neurons generate action potentials rons and efferent motoneurons (Fig. 1a). In humans, the with frequencies that correspond to the size of the sensory innervation of the muscle spindle arises from stretch and to the rate of stretching [43] (Fig. 2). Sensory both group Ia and group II afferent fibers (also some- neurons innervating bag1 fibers respond maximally to times called type Ia or type II fibers, respectively), which the velocity of changes in muscle fiber length (dynamic differ in their axonal conduction velocity [34]. In con- sensitivity) and those innervating bag2 fibers as well as trast, in mice an innervation by group II fibers has so far nuclear chain fibers respond maximally to the amount of not been detected by histological or functional assays stretch (static sensitivity). For a recent review on the [26, 35]. However, transcriptome analysis of DRG pro- mechanotransduction processes within the sensory nerve prioceptive neurons has recently suggested the existence terminal, see [45]. of group II fibers also in mice [36]. There is usually only Sensory neuron activity from muscle spindles can be a single Ia afferent fiber per spindle, and every intrafusal electrophysiologically recorded and characterized in a muscle fiber within that spindle receives innervation number of different ways. In humans, for example, indi- from that sensory neuron. In cat, rat and mice (and vidual sensory afferent (“single unit”) action potentials probably many other species), the axon terminals of this can be studied in vivo by intraneural microelectrodes sensory afferent fiber coil around the central (equatorial) inserted into accessible peripheral nerves (microneuro- part of both nuclear bag and nuclear chain fibers, form- graphy), such as the median and ulnar nerves at the ing the primary endings (also called annulospiral end- wrist or upper arm, the radial nerve in the upper arm, ings) [37, 38] (Fig. 1b). In humans, sensory terminals and the tibial and common peroneal nerves in the lower form irregular coils with branches and varicose swellings limb [29]. In mice, single unit muscle spindle afferent Fig. 2 Typical responses of a muscle spindle to stretch. The responses of an individual muscle spindle from the mouse extensor digitorum longus muscle to ramp and hold stretches applied to the tendon were recorded with an extracellular electrode. Single unit action potentials are shown in (a and d). The stretch was 4-s long, and the length change corresponded to 260 (panel b) and 780 (panel e) μm. The ramp speed in (e) was 3- fold higher compared to that in (b). Panels c and f represent the instantaneous frequencies (action potentials/s). In panel f, three different parameters that are usually analyzed to describe muscle spindle function are illustrated: resting discharge (RD), dynamic peak (DP), and static response (SR). For more information on these parameters, see [32, 33, 44]. Note that the dynamic peak and the static response is higher in (f), compared in (c) due to the higher ramp speed and the longer length change. Since the fusimotor innervation was cut during the dissection of the muscle, no action potentials can be observed directly after the end of the ramp and hold stretch (spindle pause) Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 4 of 13 responses to ramp-and-hold stretches and sinusoidal vi- muscle spindles can be recognized in fetal tissue around bratory stimuli have been well characterized in an the 11th week of gestation [52, 53], but little is known ex vivo adult mouse extensor digitorum longus prepar- about the molecular basis of human muscle spindle de- ation dissected with the innervating nerve attached [26, velopment. In contrast, muscle spindle development is 46]. A typical example for a single unit muscle spindle much better characterized in rodents, where muscle response to two different ramp-and-hold stretches in the spindle differentiation begins around embryonic day 14 adult mouse extensor digitorum longus muscle is shown when the growth cone of the sensory neuron’s axon in Fig. 2. In many species, muscle spindles exhibit a rest- reaches its target muscle. Fusimotor innervation de- ing discharge that is related to the degree of muscle velops a few days later and is present in mice at E19 stretch but the frequency of the mean firing rate differs [54]. In rodents and humans, immature myotubes are in- between species. In mice at room temperature, the fre- duced to differentiate into intrafusal fibers when sensory quency is ~ 15 Hz (Fig. 2). Muscle spindle afferents en- afferent axons contact the primary myotubes [55–57]. code muscle length in their frequency of firing, i.e. the Apparently, nuclear bag fibers differentiate before nu- more the muscle is stretched, the higher the frequency clear chain fibers in rats [58, 59]. There is the possibility (static response). In addition to the static encoding of of a hyperinnervation of intrafusal fibers with subse- length changes, spindle afferents, especially primary af- quent pruning of the terminals for the fusimotor innerv- ferents, can respond to dynamic length changes, i.e. the ation [60] as well as for the sensory innervation [61]of faster the stretch, the higher the frequency during the rat muscle spindles. In mice, the intrafusal fibers are ini- ramp phase. Accordingly, the instantaneous frequency tially surrounded by a “web-like” network of sensory (action potentials/s) shown in Fig. 2 is higher the faster axons, which is reduced to an adult primary ending from the stretch is and the longer the length change is. a single sensory neuron (Fig. 3). Human muscle spindles In addition to sensory neurons, intrafusal muscle fibers are functional at birth, but their response to stretch is are also innervated by efferent motoneurons (fusimotor immature [30]. Moreover, with the postnatal increase in innervation; Fig. 1a) [47]. Both β- and γ-motoneurons muscle mass and mobility, sensory nerve terminals in innervate intrafusal fibers, but γ-motoneurons are con- mice and humans undergo a number of anatomical and siderably more abundant and much better characterized physiological changes [62–64]. By postnatal day 18, compared to β-motoneurons [48]. Gamma-motoneurons muscle spindle afferent firing is indistinguishable from constitute about 30% of all motoneurons in the ventral the firing in adult rats suggesting that muscle spindle horn of the spinal cord. Axons of motoneurons usually maturation continues into postnatal life and that muscle enter the spindle together with the sensory fibers in the spindles are capable of responding to stretch, even at an central region but innervate intrafusal muscle fibers ex- age when their morphological and ultrastructural matur- clusively in the polar regions. The endplates of γ- ation is not yet fully accomplished [65]. motoneurons differ structurally from the neuromuscular After the establishment of a physical contact between junctions formed by α-motoneurons on extrafusal fibers, the sensory axon and the primary myotube, both cells but both are cholinergic synapses with many features in exchange inductive signals ensuring the differentiation common, including junctional folds and a basal lamina of intrafusal fiber and the survival of the sensory neuron. filling the synaptic cleft [47]. Moreover, both synapses This reciprocal signaling is essential for muscle spindle require the extracellular matrix synapse organizer agrin differentiation and intrafusal fiber development. Accord- and its receptor complex (consisting of the low-density ingly, elimination of the sensory input (but not of the lipoprotein receptor-like protein 4 and the tyrosine kin- fusimotor input) in embryonic and adult muscle spindles ase MuSK) for their formation, suggesting a common results in a rapid degeneration of the intrafusal fibers molecular basis for their synaptogenesis [49]. Gamma- ([66–68]; for review, see [55]). The key inductive factor motoneurons induce contractions of sarcomeres in the for the sensory neuron-mediated muscle spindle differ- polar region to exert tension on the central region of entiation is the immunoglobulin form of neuregulin-1 intrafusal fibers [47, 50]. This prevents the slackening of (Ig-Nrg1). Ig-Nrg1 is expressed by proprioceptive neu- intrafusal fibers during muscle shortenings and allows rons [69, 70], and its release from sensory neurons and for continuous adjustment of the mechanical sensitivity subsequent binding to the ErbB2 receptor expressed by of spindles over the wide range of muscle lengths and immature muscle fibers [71] induces their differentiation stretch velocities that occur during normal motor into intrafusal muscle fibers. Accordingly, Nrg1- or behaviors. ErbB2-deficient mice do not initiate muscle spindle dif- ferentiation, do not elaborate Ia afferent terminals and Muscle spindle development and ageing have an ataxic behavior as well as abnormal hind limb Muscle spindle development starts during embryonic reflexes, consistent with severe proprioceptive deficits stages but continues well into adult life [51]. Human [69–72]. Nrg1–ErbB2 signaling activates downstream Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 5 of 13 Fig. 3 Postnatal development of mouse muscle spindles. Muscle spindles from postnatal day 0: P0 (a), P8 (b), and P40 (c). Thy1-YFP mouse extensor digitorum longus were stained with anti-GFP antibodies. Only the central (equatorial) region is shown. Note the transformation of the “web-like” appearance of the sensory nerve terminal into the typical annulospiral ending during postnatal development. Scale bar in all panels: 50 μm targets such as the transcription factor early growth re- On the other hand, muscle fibers release sponse protein 3 (Egr3)[73–75], and the Ets transcrip- neurotrophin-3 (NT3), which activates the tropomyosin tion factors Pea3, Erm and Er81 as well as the Grb2- receptor kinase C (TrkC) receptor on proprioceptive associated binder 1 protein, a scaffolding mediator of re- sensory neurons and by this secures the survival of the ceptor tyrosine kinase signaling [69, 76, 77]. Although sensory neuron [79–81]. The TrkC/NT3 signaling sys- muscle spindles are initially generated in Egr3-deficient tem is, however, not required for the initiation of muscle mice [75], subsequently most of them degenerate, result- spindle differentiation [82]. Muscle-specific overexpres- ing in ataxic behavior [73, 74]. Overexpression of Egr3 in sion of NT3 results in an increase in the number of pro- primary myotubes on the other hand leads to their dif- prioceptive afferents and muscle spindles [83–85]. NT3/ ferentiation into intrafusal fibers [78], suggesting that TrkC signaling induces the expression of the Etv1 (Er81) this transcription factor is necessary and sufficient for transcription factor in proprioceptive sensory neurons muscle spindle maintenance. Interestingly, Ig-Nrg1 is [76, 86]. Interestingly, the survival of proprioceptive sen- the substrate for the membrane-bound aspartyl protease sory neurons supplying distinct skeletal muscles differ in Bace1 (also called β-secretase 1). Cleavage of Ig-Nrg1 is their dependence on Etv1 for their survival and differen- required for Ig-Nrg1 function and, accordingly, in the tiation [87]. The survival and/or specification of the absence of Bace1, muscle spindle numbers are reduced TrkC-positive proprioceptive afferents also requires the and spindle maturation is impaired. Moreover, a graded expression of the Runt-related transcription factor 3 reduction in Ig-Nrg1 signal strength in vivo induced by (Runx3) and Runx3-knockout mice display severe limb pharmacological Bace1 inhibition results in increasingly ataxia due to absence of proprioceptive sensory neurons severe deficits in the formation and maturation of [88, 89]. muscle spindles in combination with a reduced motor As in the musculoskeletal system in general, various coordination [70]. The continuous presence of Bace1 elements of the proprioceptive system decline during and Ig-Nrg1 is essential to maintain muscle spindles in ageing [90, 91]. These changes might contribute to the adult muscle, since either pharmacological inhibition of frequent falls and motor control problems observed in Bace1 or induced Bace1 deficiency in adult propriocep- older adults. On the structural level, muscle spindles in tive neurons also leads to a decline of muscle spindle aged humans possess fewer intrafusal fibers, an increased number [70]. In summary, the sensory neuron induces capsular thickness and some spindles which show signs the differentiation of muscle spindles from immature of denervation [92, 93]. In old rats, primary endings are myotubes via Ig-Nrg1, Bace1 and ErbB2-mediated acti- less spiral or non-spiral in appearance, but secondary vation of Egr3. endings appeared unchanged [94, 95]. Likewise, in old Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 6 of 13 mice, there is a significant increase in the number of Ia the dystrophin/DGC-mediated molecular connection afferents with large swellings that fail to properly wrap lead to mechanical lability of the sarcolemmal mem- around intrafusal muscle fibers. There is also a degener- brane and subsequent contraction-induced damage [114, ation of proprioceptive sensory neuron cell bodies in the 120–122]. While regeneration of damaged muscle fibers dorsal root ganglion but no change in the morphology occurs initially, it cannot compensate for the prolonged and number of intrafusal muscle fibers [96]. In addition, degenerative loss of muscle tissue [123], leading over electrophysiological studies showed that mature rat time to a reduction of muscle mass, loss of contractile muscle spindles display a lower dynamic response of pri- force and, in the case of DMD, to premature death of mary endings compared with those of young animals the affected person due to respiratory or cardiac muscle [94]. Taken together, the proprioceptive system under- failure [124]. goes significant structural and functional changes with Many muscular dystrophy patients suffer from postural advancing age and the changes are consistent with a instability, sudden spontaneous falls and poor manual gradual decline in proprioceptive function in elderly in- dexterity [125–128], suggesting that their proprioceptive dividuals and animals. system might be impaired. However, only minor morpho- logical changes in muscle spindles were detected in hu- Muscle spindle structure and function in muscular man dystrophic muscles. These changes primarily affect dystrophy the connective tissue surrounding intrafusal fibers. For ex- An impaired proprioception, in some cases associated ample, thickening of the capsule and of the connective tis- with an altered muscle spindle morphology, has been sue septa inside the spindle and an “oedematous swelling” documented as a secondary effect in many diseases. of the spindle were reported in muscle biopsy specimens These include Parkinson’s disease [97], Huntington’s dis- from Duchenne- and limb-girdle muscular dystrophy pa- ease [98], multiple sclerosis [99], Charcot-Marie-Tooth tients [106]. Likewise, analyses of biopsy specimens from type 2E [100], traumatic or neurotoxic injury [101], patients with muscular dystrophy and with congenital dys- spinal muscular atrophy [102], diabetic neuropathy [103, trophy revealed an increased thickness of the spindle cap- 104] and myasthenia gravis [105, 106]. In amyotrophic sule and a slight decrease of the intrafusal fiber diameter lateral sclerosis, sensory neurons are similarly affected as [129]. An autopsy study of seven DMD patients aged 15 α-motoneurons [107–110]. They accumulate misfolded to 17 years reported more severe pathological changes in- SOD1 protein and the annulospiral endings degenerate, cluding degenerative changes, atrophy and loss of intrafu- leading to ataxia and motor control problems [107, 109]. sal muscle fibers [130], but it is unclear if these more In contrast to α-motoneurons, γ-motoneurons appar- extensive changes were caused by the disease or due to ently survive degeneration in murine models of amyo- postmortem tissue degeneration. This possibility has to be trophic lateral sclerosis and spinal muscular atrophy considered, since proprioceptive functions of muscle spin- [111–113], suggesting differential vulnerabilities for both dles in DMD patients appear rather normal (see below) types of motoneurons in both diseases. and since a recent study analyzing muscle spindles from a Recently, a number of studies have analyzed proprio- 27-year-old severely affected DMD patient described that ception and muscle spindle function in patients with spindle size and number as well as the size of intrafusal muscular dystrophy and in dystrophic mouse models. myofibers and capsule thickness were in the normal range Muscular dystrophies are a heterogeneous group of [131]. Interestingly, the extrafusal fibers directly surround- more than 30 different mostly inherited diseases charac- ing the muscle spindles were also less affected by the de- terized by muscular weakness and atrophy in combin- generative events compared to fibers further away from ation with degeneration of the musculoskeletal system the spindle, suggesting the possibility of a more protective [114]. The molecular basis of many muscular dystro- environment directly around muscle spindles. phies are mutations that directly or indirectly influence Likewise, murine models for several muscular dystro- the function of the dystrophin-associated glycoprotein phies display only minor changes in muscle spindle complex (DGC) [115, 116]. The most common form of structure compared to wildtype control mice. For ex- muscle dystrophy in humans is Duchenne muscular dys- ample, muscle spindles in the soleus muscle from 1- dy-2J/dy-2J dy2J/dy2J trophy (DMD) which affects approximately 1 in 5000 year-old C57BL/6J (Lama2 ) dystrophic boys [117]. DMD is caused by mutations in the DMD mice, a model for laminin α2 (merosin)-deficient con- gene, which codes for the large cytoskeletal protein dys- genital muscular dystrophy, had a small but significant trophin [114]. In skeletal muscle, dystrophin links sub- increase in the diameter of the outer capsule and in the sarcolemmal F-actin filaments to the extracellular matrix overall thickness of the equatorial region [132]. But, as via the DGC [118, 119]. This link mechanically stabilizes in the corresponding patients, intrafusal fibers and sen- the sarcolemmal membrane particularly during muscle sory terminals appeared mostly spared from degener- mdx contraction. Mutations which cause an interruption of ation [44, 132]. Similarly, the DMD mouse line [133], Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 7 of 13 a widely used model system for muscular dystrophy of remains present at the neuromuscular junction, the the Duchenne type [134], revealed no reduction of the myotendinous junction and blood vessels [143–146]. In mdx total number of muscle spindles and no change in the extrafusal muscle fibers from DMD mice, utrophin is structure of muscle spindles and their sensory innerv- greatly upregulated and present along the entire sarco- ation [135, 136]. Thus, compared to extrafusal muscle fi- lemma [147, 148]. The upregulation of utrophin expres- bers, the morphology of intrafusal muscle fibers and of sion in extrafusal muscle fibers can lessen or even mdx muscle spindles generally appear much less affected by prevent the dystrophic phenotype in DMD mice and the degenerative processes in humans and in mice with muscular dystrophy patients [149–153]. The upregula- mdx Duchenne-type muscular dystrophy. tion of utrophin in intrafusal fibers of DMD mice The mechanism(s), which protect intrafusal myofibers might therefore functionally compensate for the absence from degeneration and wasting, are unknown. Capsular of dystrophin and prevent the degeneration of intrafusal thickening in the equatorial region may be an adaptive re- fibers. However, intrafusal muscle fibers from DMD pa- sponse, preventing the intrafusal fibers from undergoing tients are utrophin-negative [131], suggesting that the atrophy. Another explanation for the sparing of muscle upregulation of this protein cannot solely explain the spindles in DMD patients could be a better maintenance preservation of intrafusal muscle fibers in humans. of the intracellular calcium homeostasis similar to what An obvious question arising from these observations is has been described for extraocular muscles [137]. Further- whether the relatively minor structural changes in more, the mild phenotypic effect of the dystrophin muta- muscle spindles from DMD patients and corresponding tions might be due to the different surface-to-volume mouse models are accompanied by functional changes. ratio, compared to extrafusal fibers. Intrafusal fibers are Analysis of single unit sensory afferent recordings from mdx thinner compared to extrafusal fibers, have a much DMD mice showed that muscle spindles have a nor- smaller mechanical burden, and generate considerably less mal response to ramp-and-hold stretches and only a contractile force. They are therefore less likely to suffer slightly increased response to sinusoidal vibrations [136]. from mechanical damage [138]. More strikingly, the resting discharge, i.e. the action po- Immunohistochemical analysis showed that dystrophin tential frequency of sensory afferents from a resting is present in the sarcolemma of the polar regions of muscle spindle (Fig. 2), was significantly increased in mdx intrafusal fibers [139]. In contrast, in the equatorial re- DMD mice compared to control mice. This increase gion, dystrophin is absent from that part of the intrafusal in the resting discharge might be clinically relevant since fiber, which is in contact with the sensory nerve terminal it would cause an increased muscle tone via the muscle but concentrated in parts without sensory nerve contact stretch reflex, which would lead to an increase in muscle [136, 139] (Fig. 4a–d). Other proteins of the DGC (in- stiffness and an aggravation of the degenerative events in cluding alpha-dystrobrevin1; Fig. 4k) have a similar dis- extrafusal fibers of DMD patients. tribution. The area, where the DGC is concentrated, also Interestingly, a similar increase of the resting discharge −/− corresponds to the region where the intrafusal fiber has was observed in SJL-Dysf C57BL/6 (dysf ) mice [136], direct contact to the basal lamina. The interaction of a murine model system for dysferlinopathies [154, 155]. DGC components with basal lamina proteins might Dysferlinopathies (including limb girdle muscular dys- stabilize and help to maintain the subcellular concentra- trophy 2B and Miyoshi myopathy) are muscular dystro- tion of the DGC in this region of the intrafusal fiber. In phies characterized by muscle weakness and wasting but any case, the unusual distribution of DGC components differ from DMD in the molecular etiology and disease indicates a molecular specialization in particular regions progression [156]. They are caused by mutations in the of the intrafusal fiber plasma membrane. DYSF gene that impair the function of dysferlin [157– As expected, dystrophin is absent in intrafusal fibers of 159], a single pass transmembrane protein with import- mdx DMD mice [136] (Fig. 4e–g). However, utrophin ex- ant roles in membrane fusion and trafficking [156, 160, pression is markedly upregulated and has a similar dis- 161]. When microlesions in the plasma membrane mdx tribution in DMD mice as dystrophin in wildtype occur, vesicles are recruited to the injury site and dysfer- mice [136] (Fig. 1e–j). Utrophin is an autosomally lin then appears to participate in the resealing of the in- encoded paralogue of dystrophin [136]. It shares more jury site by promoting vesicle aggregation and fusion than 80% amino acid sequence similarity to dystrophin, with the plasma membrane [162, 163]. Accordingly, loss has a similar domain structure and like dystrophin can of dysferlin leads to an impaired membrane repair and interact with actin filaments and with DGC components degeneration of skeletal muscle fibers, causing the [140]. In skeletal muscle, utrophin is highly expressed in muscle weakness. Additional functions of dysferlin, in- 2+ fetal and regenerating muscle fibers [141, 142]. In adult cluding an impaired Ca homeostasis during mechan- wildtype muscle fibers, utrophin is replaced by dys- ical stress [164], might contribute to the degeneration of mdx trophin along the entire sarcolemmal membrane but skeletal muscle. Like in the DMD mouse, muscle Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 8 of 13 Fig. 4 Distribution of the dystrophin glycoprotein complex in mouse intrafusal fibers. Panel a shows two intrafusal fibers labeled by anti- dystrophin antibodies (red channel) and by antibodies against the vesicular glutamate transporter 1 (vGluT1; white channel). Panels b–d show the boxed area in panel c at a higher magnification. Note that dystrophin is concentrated in the intrafusal fiber plasma membrane in areas that are not in contact with the sensory neuron. The blue color represents nuclei stained with 4′,6-diamidin-2-phenylindol (DAPI). Panels e–j show the mdx distribution of utrophin (red channel) in the central region of muscle spindles from wildtype (e–g) and from DMD mice (h–j). Anti-vGluT1 antibodies (green channel in panels e–j) were used to label the sensory nerve terminal. Panels d, g and j show the merged channels. Utrophin is mdx not detectable in the equatorial region of muscle fibers from wildtype mice (e) but severely upregulated in intrafusal fibers from DMD mice (h). Note the absence of utrophin in the contact area between intrafusal fiber and sensory nerve terminal. Asterisks mark corresponding positions in all panels. Panel k shows a single confocal section of a muscle spindle stained with antibodies against vGluT1 (magenta) and against dystrobrevin (green) to indicate that other components of the DGC have a similar distribution as dystrophin, i.e. are concentrated in areas of the intrafusal fiber that are not in contact with the sensory nerve terminal spindle number and morphology of intrafusal fibers and patients perceive passive movements, experience illusory their innervation were not changed, but the resting dis- movement induced by muscle tendon vibration, and charge frequency was increased qualitatively and quantita- have proprioceptive-regulated sways in response to vi- mdx tively similar to DMD mice [136]. The similarity of the bratory stimulation applied to the neck and ankle muscle mdx −/− functional changes in DMD and dysf mice suggests tendons [165]. Moreover, reinforcement maneuvers in- a common deficit in both mouse strains, but the molecu- creased the sensitivity of muscle spindle afferents to im- lar mechanism is unknown. The double-mutant mice did posed movements of the ankle in a similar way in DMD not have an aggravated phenotype, suggesting that both patients and in non-affected controls [166]. These find- mutations coalesce on the same pathway [136]. ings argue for either preserved proprioceptive functions In contrast to the functional changes in murine model of muscle spindles or the activation of compensatory systems for different forms of muscular dystrophy, little mechanisms. if any functional deficits have been observed in muscular The morphological phenotype in Duchenne muscular dystrophy patients. For example, muscular dystrophy dystrophy is rather mild, but are considerably more Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 9 of 13 severe in muscle spindles from patients with myotonic been successfully used during rehabilitation to reduce dystrophy, where extensive intrafusal fiber splitting was the decline of motor control in subjects with facioscapu- reported [167, 168]. In addition, sensory endings were lohumeral muscular dystrophy [180] and with Parkinson undetectable on nuclear bag and nuclear chain fibers. In patients [181]. In muscular dystrophy patients, this train- agreement with these pronounced ultrastructural ing slows down the deleterious effects of the gradual de- changes, areflexia has been reported in myotonic dys- cline of motor abilities [166]. Since muscle spindle trophy [169], congenital dystrophies [170] and centro- afferent firing is modified by the emotional context nuclear myopathy [171], but not in patients with tibial [182], it is conceivable to exploit the emotional situation muscular dystrophy [172]. and vibrational stimuli during physical rehabilitation or In summary, studies in humans and mice with muscu- training to increase proprioceptive acuity. lar dystrophies show various degrees of impairment of Finally, muscle spindle preservation in DMD may be muscle spindle function and proprioception. The deficits an important factor to exploit new therapeutic ap- could alter joint coordination, impair movements and proaches for muscular dystrophy patients. For example, contribute to the instable gait, frequent falls and motor the strong upregulation of the utrophin expression in mdx control problems of muscular dystrophy patients. Care- intrafusal fibers from DMD mice [136] might be used givers and patients should therefore consider an im- to investigate the regulation of the utrophin expression paired proprioception when developing guidelines and in more detail. Since utrophin can functionally compen- when testing new interventions. sate dystrophin deficiency, a better understanding of the signaling cascade underlying utrophin upregulation in mdx Therapeutic strategies to improve muscle spindle DMD mice might aid in developing strategies for a function and proprioception pharmacological or genetic activation of utrophin ex- The most prevalent symptom of all muscular dystrophy pression [183], which might also be applicable to upreg- patients is the loss and wasting of skeletal muscle tissue. ulate utrophin expression in extrafusal fibers. Therefore, common therapeutic interventions for pa- In summary, therapeutic strategies for muscular dys- tients with muscular dystrophy must aim at increasing trophy patients should include in addition to strengthen- muscle strength and reducing muscle fatigue and degen- ing the contractile muscle force, the preservation of eration. A proprioceptive impairment is certainly not the muscle spindles and the sensitization of proprioception sole cause for the motor control problems in these pa- in order to maintain appropriate motor control and a tients, but the important role of the sensory system con- stable gait and posture. trolling motor coordination should not be ignored. In Abbreviations any neuromuscular disease, therapeutic strategies should CNS: Central nervous system; DAPI: 4′,6-Diamidin-2-phenylindol; DGC: Dorsal therefore also aim at restoring/maintaining propriocep- root ganglion; DMD: Duchenne muscular dystrophy; DP: Dynamic peak; ErbB2: Erb-b2 receptor tyrosine kinase 2; Egr3: Early growth response protein tion and muscle spindle function. 3; Etv1: ETS variant transcription factor 1; Ig-Nrg1: Immunoglobulin form of Several ways of improving muscle spindle function in neuregulin-1; MuSK: Muscle-specific kinase; NT3: Neurotrophin-3; P: Postnatal dystrophic patients can be envisioned. The recent identi- day; RD: Resting discharge; Runx3: Runt-related transcription factor 3; SR: Static response; TrkC receptor: Tropomyosin receptor kinase C receptor; fication of the Piezo2 channel as the primary mechano- vGluT1: Vesicular glutamate transporter 1 transduction channel [6, 173] might be exploited to develop drugs, which specifically target mechanosensitiv- Acknowledgements The author would like to thank Edith Ribot-Ciscar, Benedikt Schoser, Bob ity without interfering with extrafusal muscle fiber func- Banks and Guy Bewick for critically reading and improving the manuscript. tion or with neuromuscular transmission [174]. These The contribution of Sarah Rossmanith and Yina Zhang to Figs. 3 and 4 is drugs could either directly affect the Piezo2 channel gratefully acknowledged. [175] or indirectly, for example via modulatory Gi- Authors’ contributions coupled receptors [176]. However, potential drugs still All authors participated in the design and coordination of the text and await clinical trials and approval and side effects due to helped to draft this review. All authors prepared, read and approved the final manuscript. interference with Piezo2 channels in non-muscle tissues might limit their application [174]. Funding Alternatively, training of the proprioceptive sense is a Research in the lab of the first author is supported by the German Research Foundation (DFG; Kr1039/16), the Friedrich-Baur-Society, the German Society valuable behavioral therapy for improving impaired for Muscle Disease (DGM), the German Academic Exchange Service (DAAD), motor function and can significantly improve motor and the Munich Center for Neurosciences—Brain & Mind. control dysfunctions in many neuromuscular disorders Availability of data and materials and in aging-related proprioceptive decline [177]. Spe- Not applicable. cific proprioceptive training can improve balance control [178], motor learning [177] and walking parameters Ethics approval and consent to participate [179]. A vibratory-based proprioceptive training has Not applicable. Kröger and Watkins Skeletal Muscle (2021) 11:3 Page 10 of 13 Competing interests 23. Blumer R, Lukas JR, Aigner M, Bittner R, Baumgartner I, Mayr R. Fine The authors have no conflict of interest to report. structural analysis of extraocular muscle spindles of a two-year-old human infant. Invest Ophthalmol Vis Sci. 1999;40(1):55–64. Received: 10 November 2020 Accepted: 20 December 2020 24. Buttner-Ennever JA, Konakci KZ, Blumer R. Sensory control of extraocular muscles. Prog Brain Res. 2006;151:81–93. 25. Lienbacher K, Mustari M, Hess B, Buttner-Ennever J, Horn AK. Is there any sense in the palisade endings of eye muscles? Ann N Y Acad Sci. 2011;1233: References 1–7. 1. Sherrington CS. On the proprio-ceptive system, especially in its reflex 26. 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