Sex-dependent and muscle-specific progression of the MYBPC1 E248K Myotrem myopathy in response to aging

Dominant missense mutations in MYBPC1, the gene encoding the essential sarcomeric slow Myosin Binding Protein-C (sMyBP-C), are associated with Myotrem, a new, early-onset congenital myopathy characterized by muscle weakness, hypotonia, skeletal deformities, and myogenic tremor. Importantly, the clinical manifestation of Myotrem in mid- and late adulthood is unknown. Using the Myotrem MYBPC1 E248K-knock-in (E248K-KI) murine model, we interrogated contractile performance of soleus, gastrocnemius, and tibalis anterior (TA) muscles in both male and female mice in mid- (12 months) and late (24 months) adulthood. Our findings show that the phenotypic manifestation of E248K Myotrem differs across muscle type, sex, and age. While KI soleus muscle consistently exhibited contractile impairment across both sexes and ages, KI gastrocnemius muscle displayed preserved force production. Interestingly, TA muscle showed a sex- and age-specific effect with preserved function through 12 months in both sexes and a sharp decline at 24 months solely in males. Quantitative analysis of TA sarcomeric organization uncovered structural deficits coinciding with contractile dysfunction, supporting the notion that sMyBP-C serves a primarily structural role in skeletal muscle. Collectively, our studies reveal that aging affects the E248K Myotrem myopathy in a muscle- and sex-dependent fashion and show that sarcomeric disorganization accompanies contractile deterioration in affected muscles.