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Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle.

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.

Pubmed ID: 21285509

Authors

  • Goonasekera SA
  • Lam CK
  • Millay DP
  • Sargent MA
  • Hajjar RJ
  • Kranias EG
  • Molkentin JD

Journal

The Journal of clinical investigation

Publication Data

March 7, 2011

Associated Grants

  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Calcium
  • Creatine Kinase
  • Dystrophin
  • Gene Expression Regulation
  • Mice
  • Mice, Transgenic
  • Mitochondria
  • Muscle, Skeletal
  • Muscular Dystrophies
  • Necrosis
  • Phenotype
  • Sarcoglycans
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Transgenes