The role of the dystrophin -glycoprotein complex in the structure, function, and susceptibility to contraction -induced injury of limb muscles in dystrophic mice.

Abstract

The dystrophin glycoprotein complex (DGC) physically links cytoskeletal actin to the extracellular matrix (ECM) of skeletal muscle fibers, and mutations in the genes encoding many members of the DGC result in muscular dystrophy. Primary deficiencies of two proteins, dystrophin and alpha-sarcoglycan, destabilize the entire DGC in <italic>mdx</italic> and <italic>Sgca</italic>-null mice, respectively. The purpose was to examine the structure, function and susceptibility to contraction-induced injury of limb muscles of <italic>Sgca</italic>-null and <italic>mdx</italic> mice to elucidate the function of the DGC. The working hypothesis was that the DGC shunts contractile forces laterally from the myofibrils through the plasma membrane to the ECM, and deficiencies in the DGC result in a mechanically compromised cytoskeleton, increasing sarcomere heterogeneity and susceptibility to damage. Contractile and morphological properties of extensor digitorum longus (EDL) and soleus muscles of <italic>Sgca</italic>-null and wild type mice were compared, and the responses of muscles of <italic> Sgca</italic>-null and <italic>mdx</italic> mice to contraction-induced injury induced by single stretches were investigated. Compared with muscles of wild type mice, muscles of <italic>Sgca</italic>-null mice maintained 40% to 100% greater masses throughout the life span, resulting primarily from the accumulation of noncontractile material. Increases in fiber number provided some compensation for the presence of degenerating fibers in muscles of <italic>Sgca</italic>-null mice as evidenced by absolute forces and powers at or above control values. Similar forces and powers of alpha-sarcoglycan deficient and wild type muscles coupled with large masses of muscles of <italic> Sgca</italic>-null mice resulted in low specific forces and normalized powers. An exception was that soleus muscles of male <italic>Sgca</italic>-null mice employed additional, but as yet unknown, adaptations to compensate for the alpha-sarcoglycan deficiency resulting in control levels of specific force and normalized power. Compared with respective control muscles, greater force deficits were observed following single stretches of maximally activated EDL muscles of <italic>mdx</italic> mice and EDL and soleus muscles of <italic> Sgca</italic>-null mice with no indications of membrane damage. The findings are consistent with a role for the DGC in the stabilization of the alignment of sarcomeres, in addition to the previously accepted role in conferring structural support to the muscle fiber membrane.