G.P.108 Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy

Abstract

Abstract The expression of sarcomeric proteins is impaired in facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy characterized by muscle weakness. In addition, overexpression of DUX4, the leading FSHD candidate gene, has been shown to activate pathways involved in sarcomeric protein degradation. Here we investigated whether sarcomeric dysfunction contributes to muscle weakness, using demembranated single muscle fibers of FSHD patients and control subjects. The force generating capacity of sarcomeres is significantly impaired in FSHD. Sarcomeric weakness was restricted to type II muscle fibers, in which maximum force generation was only 70% of normal strength. In contrast to active force measurements, a 5- to 12-fold increase in passive force was seen in type I and type II fibers respectively, indicating stiffening of titin molecules. Corroborating these findings, we observed a decrease in myofilament lattice spacing and increase in calcium sensitivity, both physiological consequences of titin stiffening. Based on these findings, we propose that sarcomeric dysfunction plays a critical role in muscle weakness in FSHD.