Journal Article

Rescue of Dystrophic Skeletal Muscle by PGC-1α Involves a Fast to Slow Fiber Type Shift in the mdx Mouse

Barton, Elisabeth R., Selsby, Joshua T., Morine, Kevin J., Pendrak, Klara, Sweeney, H. Lee

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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