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

Abstract

BackgroundDuchenne 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.MethodsThe 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.ResultsWe 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.ConclusionsThese 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.

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

“…Activation of some of these transcriptional regulators, such as ERRγ (59), the androgen receptor (60), PPARδ (61), and the PGC-1 coactivators (62,63), have also been shown to improve pathology in animal models of DMD. These observations support the contention that gene regulatory pathways such as the GR-KLF15 axis ameliorate DMD via modulation of muscle metabolic programming and add to an emerging body of evidence that defines intimate functional relationships between KLF family members and nuclear receptors (23, 24, 64-66).…”

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

“…Chronic stimulation of the phenotypic modifier AMPK with the pharmacologic agonist 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) elicited numerous favorable adaptations in dystrophic muscle in the absence of any alterations in utrophin A expression (48). Furthermore, transgenic induction of the slow, oxidative myogenic program via skeletal muscle-specific overexpression of estrogen-related receptor-␥, PGC-1␣, or PGC-1␤ in mdx mice resulted in structural and functional improvements in the dystrophic pathology without any change in utrophin A content (10,40). Independent of utrophin A, the putative reason(s) for the enhanced dystrophic resistance associated with the pharmacologic or transgenic induction of the slow, oxidative myogenic program is(are) currently unknown but could be related to numerous factors such as differential sarcolemmal protein composition, oxygen transport and utilization capabilities, intracellular calcium dynamics, contractile apparatus, molecular signaling infrastructure, and autophagy (36,37).…”

“…The generation of muscle-specific transgenic or knockout dystrophic animals for factors such as GCN5, SIRT1, or AMPK would certainly advance our understanding of the molecular pathways involved in RSV-induced adaptations. To this end, studies in which these technologies have been implemented with PGC-1␣ and PGC-1␤ have expanded our knowledge with respect to the role of these coactivators in mediating neuromuscular plasticity (10,26).…”

Heme oxygenase and carbon monoxide protect from muscle dystrophy

“…The protection has widely been presumed to result from the strong PGC-1α-mediated induction of neuromuscular junction genes and, in particular of utrophin, a homolog of dystrophin that is known to be protective in DMD models. However, we recently generated mice with muscle-specific expression of peroxisome proliferator-activated receptor gamma coactivator 1-β (PGC-1β), a homolog of PGC-1α, and found that PGC-1β did not induce neuromuscular junction (NMJ) genes or utrophin itself and yet was equally protective against dystrophy in the mdx model [14]. This suggested that utrophin was not the key mediator of protection in the PGC-1α transgenic mice.…”

“…We formally tested this notion by crossing the PGC-1α-expressing mice into an mdx /utrophin −/− background, which at baseline reveal much more pronounced dystrophy, including blunted growth, kyphosis, and early lethality. PGC-1α significantly improved the dystrophic phenotype of these mice, including early lethality [14]. PGC-1α thus potently protects against dystrophy, but not via utrophin.…”