Abstract
BackgroundDuchenne 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.MethodsTwelve-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.ResultsWe 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.ConclusionsThe 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.
Highlights
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
Demonstrated that the mdx mice had a greater capacity to produce lactate. These muscles showed lower specific force than those of WT mice (Figure 1C), and fatigue testing showed that dystrophin-deficient muscle was more fatigable than that of WT mice (Figure 1D), suggesting that dystrophin deficiency leads to significant alterations in mitochondrial function and muscle metabolism
Comparison of the ratio of mitochondrial Deoxyribonucleic acid (mtDNA) to nDNA in the gastrocnemius muscle of vehicle treated and drug treated groups suggested a trend in an increase of the mtDNA in the AICAR and combination groups
Summary
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 asked whether metabolic remodeling agents that increase mitochondrial activity would improve muscle function in mdx mice. Increased PPARδ and AMPK activities have been implicated in these beneficial effects [12]. We hypothesized that exercise mimetics activating PPARδ and AMPK pathways are beneficial to dystrophin deficient skeletal muscle. We have used agonists of PPARδ (GW501516) and AMPK (AICAR) to activate beneficial endurance exercise-induced signaling pathways in mdx mice. We have demonstrated that endurance mimetics can improve muscle function by halting the cycle of muscle regeneration/degeneration in dystrophin-deficient mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
