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Cell Death Differ. 2017 Feb;24(2):330-342. doi: 10.1038/cdd.2016.127. Epub 2016 Nov 11.

Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy.

Author information

1
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.
2
Institute for Biomedical Sciences, The George Washington University, 2300 Eye Street, N.W., Ross 605, Washington, DC 20037, USA.
3
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
4
Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
5
Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.

Abstract

Dystrophin deficiency is the genetic basis for Duchenne muscular dystrophy (DMD), but the cellular basis of progressive myofiber death in DMD is not fully understood. Using two dystrophin-deficient mdx mouse models, we find that the mitochondrial dysfunction is among the earliest cellular deficits of mdx muscles. Mitochondria in dystrophic myofibers also respond poorly to sarcolemmal injury. These mitochondrial deficits reduce the ability of dystrophic muscle cell membranes to repair and are associated with a compensatory increase in dysferlin-mediated membrane repair proteins. Dysferlin deficit in mdx mice further compromises myofiber cell membrane repair and enhances the muscle pathology at an asymptomatic age for dysferlin-deficient mice. Restoring partial dystrophin expression by exon skipping improves mitochondrial function and offers potential to improve myofiber repair. These findings identify that mitochondrial deficit in muscular dystrophy compromises the repair of injured myofibers and show that this repair mechanism is distinct from and complimentary to the dysferlin-mediated repair of injured myofibers.

PMID:
27834955
PMCID:
PMC5299714
DOI:
10.1038/cdd.2016.127
[Indexed for MEDLINE]
Free PMC Article

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