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Open Access Research

Dystrophin deficiency exacerbates skeletal muscle pathology in dysferlin-null mice

Renzhi Han1, Erik P Rader234, Jennifer R Levy234, Dimple Bansal234 and Kevin P Campbell234*

Author Affiliations

1 Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60558, USA

2 Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, The University of Iowa, 285 Newton Road, 4283 CBRB, Iowa City, IA 52242, USA

3 Department of Neurology, Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, The University of Iowa, 285 Newton Road, 4283 CBRB, Iowa City, IA 52242, USA

4 Department of Internal Medicine, Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, The University of Iowa, 285 Newton Road, 4283 CBRB, Iowa City, IA 52242, USA

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

Published: 1 December 2011

Abstract

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 β-dystroglycan. This link extends to the extracellular matrix by β-dystroglycan's interaction with α-dystroglycan, which binds extracellular matrix proteins, including laminin α2, agrin and perlecan, that possess laminin globular 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 sarcolemma in skeletal muscle. Because dysferlin and dystrophin play different roles in maintaining muscle cell integrity, we hypothesized that disrupting sarcolemmal 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 our hypothesis, we generated dystrophin/dysferlin double-knockout (DKO) mice 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 mice or dysferlin-null mice, and, importantly, the onset of the muscle pathology occurred much earlier than it did in 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. 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 muscles or dysferlin-null muscles, suggesting that dysferlin is required for the initial recovery from lengthening contraction-induced muscle injury of the dystrophin-glycoprotein complex-compromised muscles.

Conclusions

The results of our study suggest 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. Dystrophin/dysferlin-deficient mice provide a very useful model with which to evaluate the effectiveness of therapies designed to treat dysferlin deficiency.

Keywords:
dysferlin; dystrophin; membrane repair; sarcolemmal integrity