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

PLoS One. 2012;7(1):e30063. doi: 10.1371/journal.pone.0030063. Epub 2012 Jan 11.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Body Weight / drug effects
  • Dependovirus / drug effects
  • Dependovirus / metabolism
  • Dietary Supplements
  • Gene Transfer Techniques
  • Mice
  • Mice, Inbred mdx
  • 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*
  • Muscular Dystrophy, Animal / complications
  • Muscular Dystrophy, Animal / physiopathology*
  • Myosins / metabolism
  • Organ Size
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Recovery of Function / drug effects
  • Recovery of Function / physiology*
  • Resveratrol
  • Stilbenes / administration & dosage
  • Stilbenes / pharmacology
  • Trans-Activators / metabolism*
  • Transcription Factors

Substances

  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Stilbenes
  • Trans-Activators
  • Transcription Factors
  • Myosins
  • Resveratrol