Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin

DSpace/Manakin Repository

Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin

Citable link to this page

 

 
Title: Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin
Author: Chan, Mun Chun; Rowe, Glenn C; Raghuram, Srilatha; Patten, Ian S; Farrell, Caitlin; Arany, Zolt

Note: Order does not necessarily reflect citation order of authors.

Citation: Chan, Mun Chun, Glenn C Rowe, Srilatha Raghuram, Ian S Patten, Caitlin Farrell, and Zolt Arany. 2014. “Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin.” Skeletal Muscle 4 (1): 2. doi:10.1186/2044-5040-4-2. http://dx.doi.org/10.1186/2044-5040-4-2.
Full Text & Related Files:
Abstract: Background: Duchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α improves skeletal muscle function in the murine “mdx” model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1α include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction. Methods: The effects of transgenic overexpression of PGC-1β, a homolog of PGC-1α in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1α confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1α transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1α overexpression on muscle structure and function in mdx mice. Results: We show here that PGC-1β does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1β transgenesis protects as efficaciously as PGC-1α against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1α is overexpressed in mdx/utrn-/- mice, we find that PGC-1α dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1α overexpression to show that PGC-1α can protect against dystrophy even if activated post-natally, a more plausible therapeutic option. Conclusions: These data demonstrate that PGC-1α can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1α is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1β as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1α and PGC-1β protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.
Published Version: doi:10.1186/2044-5040-4-2
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914847/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879937
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters