Journal
PLOS ONE
Volume 7, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0030063
Keywords
-
Categories
Funding
- Center for Integrated Animal Genomics
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [U54AR052646-03]
- [F32AR055005-01]
Ask authors/readers for more resources
Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic overexpression of PGC-1 alpha has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1 alpha 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-1 alpha 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-1 alpha. PGC-1 alpha 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-1 alpha over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1 alpha 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-1 alpha pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available