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

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)-1 alpha 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-1 alpha 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-1 beta, a homolog of PGC-1 alpha in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1 alpha confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1 alpha 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-1 alpha overexpression on muscle structure and function in mdx mice. Results: We show here that PGC-1 beta does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1 beta transgenesis protects as efficaciously as PGC-1 alpha against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1 alpha is overexpressed in mdx/utrn(-/-) mice, we find that PGC-1 alpha dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1 alpha overexpression to show that PGC-1 alpha can protect against dystrophy even if activated post-natally, a more plausible therapeutic option. Conclusions: These data demonstrate that PGC-1 alpha can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1 alpha 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-1 beta as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1 alpha and PGC-1 beta protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.