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Muscular dystrophy is a severe degenerative disorder of skeletal muscle characterized by progressive muscle weakness. One subgroup of this disease is caused by a defect in the gene encoding one of the components of the dystrophin–glycoprotein complex, resulting in a significant disruption of membrane integrity and/or stability and, consequently, a sustained increase in the cytosolic Ca 2+  concentration ([Ca 2+ ] i ). In the present study, we demonstrate that muscular dystrophy is ameliorated in two animal models, dystrophin-deficient  mdx  mice and δ-sarcoglycan-deficient BIO14.6 hamsters by dominant-negative inhibition of the transient receptor potential cation channel, TRPV2, a principal candidate for Ca 2+ -entry pathways. When transgenic (Tg) mice expressing a TRPV2 mutant in muscle were crossed with  mdx  mice, the [Ca 2+ ] i  increase in muscle fibers was reduced by dominant-negative inhibition of endogenous TRPV2. Furthermore, histological, biochemical and physiological indices characterizing dystrophic pathology, such as an increased number of central nuclei and fiber size variability/fibrosis/apoptosis, elevated serum creatine kinase levels, and reduced muscle performance, were all ameliorated in the  mdx /Tg mice. Similar beneficial effects were also observed in the muscles of BIO14.6 hamsters infected with adenovirus carrying mutant TRPV2. We propose that TRPV2 is a principal Ca 2+ -entry route leading to a sustained [Ca 2+ ] i  increase and muscle degeneration, and that it is a promising therapeutic target for the treatment of muscular dystrophy.

Dominant-negative inhibition of Ca 2+ influx via TRPV2 ameliorates muscular dystrophy in animal models