Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy.
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.
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.|Institute for Biomedical Sciences, The George Washington University, 2300 Eye Street, N.W., Ross 605, Washington, DC 20037, USA.
Maria C
MC
Vila
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.
Sree
S
Rayavarapu
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.
Marshall W
MW
Hogarth
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.
Jack H
JH
Van der Meulen
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.|Institute for Biomedical Sciences, The George Washington University, 2300 Eye Street, N.W., Ross 605, Washington, DC 20037, USA.
Adam
A
Horn
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.
Aurelia
A
Defour
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Shin'ichi
S
Takeda
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.|Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Kristy J
KJ
Brown
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.|Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Yetrib
Y
Hathout
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.|Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Kanneboyina
K
Nagaraju
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue NW, Washington, DC 20010, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.|Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Jyoti K
JK
Jaiswal
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D000073939:Dysferlin / Q000172:deficiency / Q000235:genetics; D016189:Dystrophin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology; D059008:Time-Lapse Imaging
D000073939:Dysferlin; D016189:Dystrophin; D053583:Interleukin-1beta; D020319:Oligodeoxyribonucleotides, Antisense; D019289:Pyruvic Acid