TY - JOUR
AU - Poggesi, C.
AB - Background: Familial hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in genes encoding sarcomeric proteins. It has been hypothesized that these mutations increase ATP utilization for sarcomere contraction and thereby increase energy demand of the heart. Previous studies in single left ventricular myofibrils from myocardium harboring the first identified causal HCM mutation R403Q in the gene (MYH7) encoding β-myosin heavy chain revealed increased kinetics suggesting a 3-fold increase in energy cost of tension generation. In the present study we investigated if sarcomere contraction is indeed less economic in human hearts harboring the heterozygous R403Q mutation or a homozygous troponin T mutation (TNNT2/K280N).Methods and results: Force generating capacity and ATP utilization were simultaneously measured at maximal and submaximal activating calcium concentrations in muliticellular muscle strips to determine economy of sarcomere contraction defined as tension cost (ATP needed for force generation). Measurements in HCM samples with MYH7 (MYH7/R403Q) and TNNT2 (TNNT2/K280N) mutations were compared with control samples from sarcomere mutation-negative patients (HCMsmn) and patients with secondary left ventricular hypertrophy due to aortic stenosis (LVHao). A significantly higher tension cost of sarcomere contraction was found in MYH7R/403Q and TNNT2/K280N compared to HCMsmn and LVHao at maximal and submaximal activation. Exchange of endogenous mutant troponin T in the TNNT2/K280N sample with recombinant wild-type troponin restored economy of muscle contraction to values found in the controls. This proves that the mutant troponin T protein increases ATP utilization to generate a certain amount of force.Conclusion: We provide direct evidence that expression of HCM-associated mutations in the heart decreases the economy of myocardial contraction at the level of the sarcomeres. Inefficient contractility may underlie cardiac dysfunction at an early stage of HCM.
TI - Increased energy utilization for force generation in human familial hypertrophic cardiomyopathy caused by sarcomere gene mutations
JF - European Heart Journal
DO - 10.1093/eurheartj/eht309.P4192
DA - 2013-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/increased-energy-utilization-for-force-generation-in-human-familial-mbn5tceDfQ
SP - P4192
VL - 34
IS - suppl_1
DP - DeepDyve
ER -