Rescue of dystrophic skeletal muscle by PGC-1α involves a fast to slow fiber type shift in the mdx mouse

• Published in: PloS one 2012, Vol.7 (1), p.e30063-e30063
• Main Authors: Selsby, Joshua T, Morine, Kevin J, Pendrak, Klara, Barton, Elisabeth R, Sweeney, H Lee
• Format: Article
• Language: English
• Subjects: Animals; Biology; Biomechanical Phenomena; Body Weight - drug effects; Contraction; Crack propagation; Dependovirus - drug effects; Dependovirus - metabolism; Dietary Supplements; Dystrophin; Fatigue; Fatigue failure; Fatigue strength; Fibers; Gene expression; Gene therapy; Gene Transfer Techniques; Glycoproteins; Histology; Insulin-like growth factors; Localization; Medicine; Mice; Mice, Inbred mdx; Mitochondria; mRNA; Muscle Contraction; Muscle Fatigue; Muscle Fibers, Fast-Twitch - drug effects; Muscle Fibers, Fast-Twitch - pathology; Muscle Fibers, Slow-Twitch - drug effects; Muscle Fibers, Slow-Twitch - pathology; Muscle function; Muscles; Muscular dystrophy; Muscular Dystrophy, Animal - complications; Muscular Dystrophy, Animal - physiopathology; Musculoskeletal system; Myosin; Myosins - metabolism; Neonates; Organ Size; Overexpression; Oxidation resistance; Oxidative stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pharmacology; Phosphorylation; Physiology; Proteins; Recovery of Function - drug effects; Recovery of Function - physiology; Resveratrol; Rodents; Signal transduction; Signaling; Skeletal muscle; Stilbenes - administration & dosage; Stilbenes - pharmacology; Trans-Activators - metabolism; Transcription Factors; Transgenic; Utrophin; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030063

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.