[HTML][HTML] Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle

SA Goonasekera, CK Lam, DP Millay… - The Journal of …, 2011 - Am Soc Clin Investig
SA Goonasekera, CK Lam, DP Millay, MA Sargent, RJ Hajjar, EG Kranias, JD Molkentin
The Journal of clinical investigation, 2011Am Soc Clin Investig
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 Ca2+ 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 …
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 Ca2+ 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 Ca2+ 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 Ca2+ reuptake that characterizes dystrophic myofibers and reduced total cytosolic Ca2+. Further, SERCA1 overexpression almost completely rescued the dystrophic phenotype in a mouse model of MD driven solely by Ca2+ influx. Mitochondria isolated from the muscle of SERCA1-Sgcd–/– mice were no longer swollen and calpain activation was reduced, suggesting protection from Ca2+-driven necrosis. Our results suggest a novel therapeutic approach using SERCA1 to abrogate the altered intracellular Ca2+ levels that underlie most forms of MD.
The Journal of Clinical Investigation