Inherited hypertrophic cardiomyopathy (HCM) is considered a disease of the cardiac sarcomere caused by pathogenic variants present in genes that encode sarcomeric proteins. The human TNNC1 gene is a designated HCM-susceptibility gene that encodes the troponin C protein expressed in both cardiac and type I slow skeletal muscles and abbreviated as cTnC and/or ssTnC, respectively. HCM patients have been reported to exhibit skeletal muscle weakness and reduced exercise tolerance; a subset of these patients has TNNC1 cardiac pathogenic variants also expressed in the slow skeletal muscle fibers. We hypothesized that the presence of TNNC1 HCM variants in slow skeletal muscle may decrease force generating capabilities and fatigue resistance of these muscles, e.g., soleus with a high percentage of type I fiber content. To address this, we examined the impact of HCM Tnnc1 mutants in mice. We isolated soleus muscles from HCM knock-in mouse models A8V heterozygous (+/−) and homozygous (−/−) and C84Y heterozygous (+/−) and their respective controls. We found that A8V (−/−) soleus muscles had lower tetanic force production and reduced fatigue resistance. Fiber type analysis revealed no differences in fiber content in either mouse model. Comparing the cross-sectional areas of Type I fibers in soleus muscles revealed significantly lower average values for A8V+/− while these values were slightly higher in C84Y+/− relative to controls. Histological evaluation of soleus muscle obtained from A8V+/− mice revealed more central nucleation, indicative of muscle regeneration. Serum myokines were measured and changes detected were consistent with HCM disease for both mouse models whereas others were consistent with lower physical activity in the A8V+/− mice. These results demonstrate that the HCM A8V mutant decreases tetanic force production in soleus muscle that may be attributed to myopathic changes in type I fibers.
Patel et al. (Sun,) studied this question.