title: Rescue of dystrophic skeletal muscle by PGC-1α involves a fast to slow fiber type shift in the mdx mouse.
abstract: Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic over-expression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle.
authors.affiliation: Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Selsby
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Morine
authors.forename: Klara
authors.initials: K
authors.lastname: Pendrak
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Barton
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001835:Body Weight / Q000187:drug effects; D000229:Dependovirus / Q000187:drug effects / Q000378:metabolism; D019587:Dietary Supplements; D018014:Gene Transfer Techniques; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction; D018763:Muscle Fatigue; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000473:pathology*; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000150:complications / Q000503:physiopathology*; D009218:Myosins / Q000378:metabolism; D009929:Organ Size; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; D009218:Myosins; D000077185:Resveratrol