Skeletal Muscle Lacking the Extreme C-Terminal SH3 Domain of Nebulin Exhibits Heightened Vulnerability to Eccentric Contraction-Induced Injury

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Nemaline myopathy is a congenital myopathy afflicting roughly 1 in 50,000 children. Nemaline myopathy is a disease of the thin filament, and mutations in the giant thin filament template nebulin contribute to its etiology. A clinical case report has demonstrated that loss of the extreme C-terminal Src homology 3 (SH3) domain of nebulin can cause nemaline myopathy. The nebulin SH3 domain is believed to anchor the thin filament to the Z-disk through its interaction with myopalladin. To further elucidate the physiological roles of the nebulin SH3 domain, the skeletal muscle phenotype of wild-type (nebulin+/+) mice was compared to that of mice homozygous for the I6611X mutation in the nebulin gene (nebulinI6611X/I6611X). The I6611X mutation introduces a premature truncation of the nebulin transcript and eliminates the SH3 domain from the nebulin protein. Contractile measurements revealed that baseline isometric stress production was identical in nebulinI6611X/I6611X and nebulin+/+ muscle (247±6 kPa vs. 253±6 kPa, respectively; P=0.50). However, nebulinI6611X/I6611X muscle exhibited a greater vulnerability to eccentric contraction-induced injury compared to nebulin+/+ muscle, where “injury” was defined as a decline in isometric stress production across a series of 10 eccentric contractions (39.3±0.8% vs. 29.1±1.6%, respectively; P<0.01). The corresponding decline in passive stiffness was identical in nebulinI6611X/I6611X and nebulin+/+ muscle (13.5±2.4% vs. 14.4±2.1%, respectively; P=0.79). Muscle fiber type distributions and cross-sectional areas were also identical in nebulinI6611X/I6611X and nebulin+/+ muscle. These data indicate that the nebulin SH3 domain is dispensable for isometric stress production in skeletal muscle but necessary for protecting muscle from injurious eccentric contractions. It is conceivable that heightened vulnerability to eccentric contraction-induced muscle injury, or to other types of biomechanical challenges, explains the pathology observed in children with nemaline myopathy.