Research

Dystrophin deficiency exacerbates skeletal muscle pathology in dysferlin-null mice

Renzhi Han, Erik P Rader, Jennifer R Levy, Dimple Bansal and Kevin P Campbell

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Skeletal Muscle 2011, 1:35 doi:10.1186/2044-5040-1-35

Published: 1 December 2011

Abstract (provisional)

Background

Mutations in the genes coding for either dystrophin or dysferlin cause distinct forms of muscular dystrophy. Dystrophin links the cytoskeleton to the sarcolemma through direct interaction with beta-dystroglycan. This link extends to the extracellular matrix via beta-dystroglycan interacting with alpha-dystroglycan, which binds extracellular matrix proteins including laminin alpha2, agrin and perlecan that possess laminin globular (LG) domains. The absence of dystrophin disrupts this link leading to compromised muscle sarcolemmal integrity. Dysferlin, on the other hand, plays an important role in the Ca2+-dependent membrane repair of damaged sarcolemmal in skeletal muscle. Since dysferlin and dystrophin play different roles in maintaining muscle cell integrity, we hypothesize that disrupting sarcolemma integrity with dystrophin deficiency would exacerbate the pathology in dysferlin-null mice and allow further characterization of the role of dysferlin in skeletal muscle.

Methods

To test this hypothesis, we generated mice lacking both dystrophin and dysferlin (DKO) by breeding mdx mice with dysferlin-null mice, and analyzed the effects of a combined deficiency of dysferlin and dystrophin on muscle pathology and sarcolemmal integrity.

Results

The DKO mice exhibited more severe muscle pathology than either mdx or dysferlin-null mice and importantly, the onset of the muscle pathology is much earlier than dysferlin deficient mice. The DKO mice showed muscle pathology of various skeletal muscles, including the mandible muscles, as well as a greater number of regenerating muscle fibers, higher serum creatine kinase levels and elevated Evans blue dye uptake into skeletal muscles. Compromised dystrophin-glycoprotein complex (DGC) expression at the sarcolemma was demonstrated in both mdx and DKO muscles by immunofluorescence analyses. Lengthening contractions caused similar force deficits regardless of dysferlin expression. However, the rate of force recovery within 45 minutes following lengthening contractions was hampered in DKO muscles compared to mdx or dysferlin-null muscles, suggesting that dysferlin is required for the initial recovery from lengthening contractions-induced muscle injury of the DGC-compromised muscles.

Conclusions

In summary, our study suggests that dysferlin-mediated membrane repair helps to limit the dystrophic changes in dystrophin-deficient skeletal muscle. Dystrophin deficiency unmasks the function of dysferlin in membrane repair during lengthening contractions. Finally, dystrophin/dysferlin deficient mice provide a very useful model to evaluate the effectiveness of therapies designed to treat dysferlin deficiency.