title: Myofiber-specific inhibition of TGFβ 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)-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) truncation mutant. Expression of dnTGFβRII in myofibers mitigated the dystrophic phenotype observed in δ-sarcoglycan-null (Sgcd(-/-)) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGFβRII 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 dnTGFβRII-mediated protection, one of which was induction of the antioxidant protein metallothionein (Mt). Indeed, TGFβ directly inhibited Mt gene expression in vitro, the dnTGFβRII 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 TGFβ signaling in MD.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Accornero
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Onur
authors.initials: O
authors.lastname: Kanisicak
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Andoria
authors.initials: A
authors.lastname: Tjondrokoesoemo
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Aria C
authors.initials: AC
authors.lastname: Attia
authors.affiliation: Department of Medicine, Section of Cardiology, 5841 S, Maryland, MC 6088, Chicago, IL 60637, USA and.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, USA jeff.molkentin@cchmc.org.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004179:Cobra Cardiotoxin Proteins / Q000494:pharmacology; D003439:Crotoxin / Q000494:pharmacology; D004195:Disease Models, Animal; D004338:Drug Combinations; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics*; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D019076:Transgenes
chemical_list: D004179:Cobra Cardiotoxin Proteins; D004338:Drug Combinations; D017382:Reactive Oxygen Species; D018125:Receptors, Transforming Growth Factor beta; D049031:Sarcoglycans; D016212:Transforming Growth Factor beta; C084936:cardiotoxin, crotoxin drug combination; D003439:Crotoxin; D008668:Metallothionein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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