15. SKELETAL MUSCLE LACKING THE EXTREME C-TERMINAL SH3 DOMAIN OF NEBULIN EXHIBITS HEIGHTENED VULNERABILITY TO ECCENTRIC CONTRACTION-INDUCED INJURY

Department: Bioengineering
Faculty Advisor(s): Richard L. Lieber

Primary Student
Name: David Samuel Gokhin
Email: dgokhin@ucsd.edu
Phone: 858-552-8585
Grad Year: 2009

Abstract
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 report has demonstrated that loss of the extreme C-terminal 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 (WT) mice was compared to that of mice homozygous for the I6611X mutation in the nebulin gene (MUT). The I6611X mutation introduces a premature truncation in the nebulin transcript and eliminates the SH3 domain from the nebulin protein. Baseline isometric stress production was identical in MUT and WT muscle (247±6 kPa vs. 253±6 kPa, respectively; p=0.50). However, MUT muscle exhibited a greater vulnerability to eccentric contraction-induced injury compared to WT 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 MUT and WT 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 MUT and WT muscle. These data indicate that the nebulin SH3 domain is dispensable for baseline isometric stress production in skeletal muscle but critical for protecting muscle from the injurious loads borne during eccentric contractions. It is conceivable that heightened vulnerability to eccentric contraction-induced muscle injury, or to other types of biomechanical challenges, is an explanation for the pathology observed in children with nemaline myopathy.

Related Links:

1. http://muscle.ucsd.edu/

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