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Myofiber-specific inhibition of TGF? signaling protects skeletal muscle from injury and dystrophic disease in mice.

ABSTRACT: Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-? has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGF?-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGF? signaling owing to expression of a TGF? type II receptor dominant-negative (dnTGF?RII) truncation mutant. Expression of dnTGF?RII in myofibers mitigated the dystrophic phenotype observed in ?-sarcoglycan-null (Sgcd(-/-)) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGF?RII transgene also reduced muscle injury and improved muscle regeneration after cardiotoxin injury, as well as increased satellite cell numbers and activity. An unbiased global expression analysis revealed a number of potential mechanisms for dnTGF?RII-mediated protection, one of which was induction of the antioxidant protein metallothionein (Mt). Indeed, TGF? directly inhibited Mt gene expression in vitro, the dnTGF?RII transgene conferred protection against reactive oxygen species accumulation in dystrophic muscle and treatment with Mt mimetics protected skeletal muscle upon injury in vivo and improved the membrane stability of dystrophic myofibers. Hence, our results show that the myofibers are central mediators of the deleterious effects associated with TGF? signaling in MD.

SUBMITTER: Accornero F

PROVIDER: S-EPMC4271062 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice.

Accornero Federica F Kanisicak Onur O Tjondrokoesoemo Andoria A Attia Aria C AC McNally Elizabeth M EM Molkentin Jeffery D JD

Human molecular genetics 20140808 25

Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-β has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFβ-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGFβ signaling owing to expression of a TGFβ type II receptor dominant-negative (dnTGFβRII) trun ...[more]

PMID: 25106553

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Project description:BACKGROUND:In muscular dystrophy and old age, skeletal muscle repair is compromised leading to fibrosis and fatty tissue accumulation. Therefore, therapies that protect skeletal muscle or enhance repair would be valuable medical treatments. Hypoxia-inducible factors (HIFs) regulate gene transcription under conditions of low oxygen, and HIF target genes EPO and VEGF have been associated with muscle protection and repair. We tested the importance of HIF activation following skeletal muscle injury, in both a murine model and human volunteers, using prolyl hydroxylase inhibitors that stabilize and activate HIF. METHODS:Using a mouse eccentric limb injury model, we characterized the protective effects of prolyl hydroxylase inhibitor, GSK1120360A. We then extended these studies to examine the impact of EPO modulation and infiltrating immune cell populations on muscle protection. Finally, we extended this study with an experimental medicine approach using eccentric arm exercise in untrained volunteers to measure the muscle-protective effects of a clinical prolyl hydroxylase inhibitor, daprodustat. RESULTS:GSK1120360A dramatically prevented functional deficits and histological damage, while accelerating recovery after eccentric limb injury in mice. Surprisingly, this effect was independent of EPO, but required myeloid HIF1?-mediated iNOS activity. Treatment of healthy human volunteers with high-dose daprodustat reduced accumulation of circulating damage markers following eccentric arm exercise, although we did not observe any diminution of functional deficits with compound treatment. CONCLUSION:The results of these experiments highlight a novel skeletal muscle protective effect of prolyl hydroxylase inhibition via HIF-mediated expression of iNOS in macrophages. Partial recapitulation of these findings in healthy volunteers suggests elements of consistent pharmacology compared to responses in mice although there are clear differences between these two systems.

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Myofiber-specific inhibition of TGF? signaling protects skeletal muscle from injury and dystrophic disease in mice.

Publications

Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice.

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