Open Access Highly Accessed Research

Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model

Vanessa E Jahnke1, Jack H Van Der Meulen1, Helen K Johnston12, Svetlana Ghimbovschi1, Terrence Partridge12, Eric P Hoffman12 and Kanneboyina Nagaraju123*

Author Affiliations

1 Center for Genetic Medicine Research, Children’s National Medical Center, Washington, DC, USA

2 Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

3 Integrative Systems Biology and Pediatrics, Research Center for Genetic Medicine Children's National Medical Center, 111 Michigan Avenue, NW Washington, DC, 20010, USA

For all author emails, please log on.

Skeletal Muscle 2012, 2:16  doi:10.1186/2044-5040-2-16

Published: 21 August 2012

Abstract

Background

Duchenne muscular dystrophy is a genetic disease involving a severe muscle wasting that is characterized by cycles of muscle degeneration/regeneration and culminates in early death in affected boys. Mitochondria are presumed to be involved in the regulation of myoblast proliferation/differentiation; enhancing mitochondrial activity with exercise mimetics (AMPK and PPAR-delta agonists) increases muscle function and inhibits muscle wasting in healthy mice. We therefore asked whether metabolic remodeling agents that increase mitochondrial activity would improve muscle function in mdx mice.

Methods

Twelve-week-old mdx mice were treated with two different metabolic remodeling agents (GW501516 and AICAR), separately or in combination, for 4 weeks. Extensive systematic behavioral, functional, histological, biochemical, and molecular tests were conducted to assess the drug(s)' effects.

Results

We found a gain in body and muscle weight in all treated mice. Histologic examination showed a decrease in muscle inflammation and in the number of fibers with central nuclei and an increase in fibers with peripheral nuclei, with significantly fewer activated satellite cells and regenerating fibers. Together with an inhibition of FoXO1 signaling, these results indicated that the treatments reduced ongoing muscle damage.

Conclusions

The three treatments produced significant improvements in disease phenotype, including an increase in overall behavioral activity and significant gains in forelimb and hind limb strength. Our findings suggest that triggering mitochondrial activity with exercise mimetics improves muscle function in dystrophin-deficient mdx mice.

Keywords:
Duchenne muscular dystrophy; Muscle; AICAR; GW501516; Metabolism