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: Joshua T Selsby, Kevin J Morine, Klara Pendrak, Elisabeth R Barton, H Lee Sweeney
• Journal: PloS one (PLoS One) Vol. 7 Issue 1 Pg. e30063 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22253880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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