G.P.49 Muscle-specific overexpression of caveolin 3 causes muscle atrophy, but not muscular dystrophy

Abstract

Caveolin, a structural membrane protein of caveolae regulates signal transduction and vesicular trafficking events as a scaffolding protein. Upregulation of caveolin 3, the muscle-specific isoform of caveolin has been shown in several muscular dystrophies, including Duchenne’s muscular dystrophy, sarcoglycan-deficient muscular dystrophy, and merosin-deficient congenital muscular dystrophy. A previous genetic study revealed systemic overexpression of caveolin 3 induces severe dystrophic changes in skeletal and cardiac muscles. However, it has uncovered how increased caveolin 3 confined in muscles participates in the mechanism leading to muscular dystrophies. In order to address the question, we generated transgenic (Tg) mice overexpressing caveolin-3 in skeletal and cardiac muscles. Mouse caveolin 3 was expressed under the control of 6.5kb of muscle creatinine kinase gene promotor/enhancer sequences. The Tg mice exhibited the delay of body weight gain and the decrease of grip strength. Skinned hind limb of the mice showed muscle atrophy, compared with wild-type littermates. The weight of individual muscles in the Tg mice was lighter than in the wild-type mice. Morphometric analysis of the single-myofiber area showed myofiber hypotrophy with increased levels of caveolin 3 protein in the cytoplasm as well as in the sarcolemma. Moreover, cardiac overexpression of caveolin 3 reduced cardiac size. Our results indicate that the muscle-specific upregulation of caveolin 3 result in muscle atrophy, but not in muscular dystrophy. Further studies have been on going to explore the precise roles of caveolin 3 in the pathogenesis of muscular dystrophy.