title: Mitigation of muscular dystrophy in mice  by SERCA overexpression in skeletal muscle.
abstract: Muscular dystrophies (MDs) comprise a group of degenerative muscle disorders characterized by progressive muscle wasting and often premature death. The primary defect common to most MDs involves disruption of the dystrophin-glycoprotein complex (DGC). This leads to sarcolemmal instability and Ca(2+) influx, inducing cellular necrosis. Here we have shown that the dystrophic phenotype observed in δ-sarcoglycan–null (Sgcd(–/–)) mice and dystrophin mutant mdx mice is dramatically improved by skeletal muscle–specific overexpression of sarcoplasmic reticulum Ca(2+) ATPase 1 (SERCA1). Rates of myofiber central nucleation, tissue fibrosis, and serum creatine kinase levels were dramatically reduced in Sgcd(–/–) and mdx mice with the SERCA1 transgene, which also rescued the loss of exercise capacity in Sgcd(–/–) mice. Adeno-associated virus–SERCA2a (AAV-SERCA2a) gene therapy in the gastrocnemius muscle of Sgcd(–/–) mice mitigated dystrophic disease. SERCA1 overexpression reversed a defect in sarcoplasmic reticulum Ca(2+) reuptake that characterizes dystrophic myofibers and reduced total cytosolic Ca(2+). Further, SERCA1 overexpression almost completely rescued the dystrophic phenotype in a mouse model of MD driven solely by Ca(2+) influx. Mitochondria isolated from the muscle of SERCA1-Sgcd(–/–) mice were no longer swollen and calpain activation was reduced, suggesting protection from Ca(2+)-driven necrosis. Our results suggest a novel therapeutic approach using SERCA1 to abrogate the altered intracellular Ca(2+) levels that underlie most forms of MD.
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio 45229, USA.
authors.forename: Sanjeewa A
authors.initials: SA
authors.lastname: Goonasekera
authors.forename: Chi K
authors.initials: CK
authors.lastname: Lam
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Millay
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sargent
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003402:Creatine Kinase / Q000235:genetics; D016189:Dystrophin / Q000235:genetics*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology*; D009336:Necrosis; D010641:Phenotype; D049031:Sarcoglycans / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes
chemical_list: C506944:Atp2a1 protein, mouse; D016189:Dystrophin; D049031:Sarcoglycans; D003402:Creatine Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium