| First Author | Goonasekera SA | Year | 2011 |
| Journal | J Clin Invest | Volume | 121 |
| Issue | 3 | Pages | 1044-52 |
| PubMed ID | 21285509 | Mgi Jnum | J:171822 |
| Mgi Id | MGI:5000161 | Doi | 10.1172/JCI43844 |
| Citation | Goonasekera SA, et al. (2011) Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. J Clin Invest 121(3):1044-52 |
| abstractText | 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 delta-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. |
