The pathophysiological role of stretch activated channel(TRPV2) in cardiomypathy and heart failure

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Muscular dystrophy is a severe degenerative disorder of skeletal muscles 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 significant disruption of membrane integrity and/or stability, and consequently a sustained increase in the cytosolic Ca^<2+> concentration([Ca^<2+>]_i). Here, we demonstrate that muscular dystrophy in two animal models, dystrophin-deficient mdx mice and δ-sarcoglycan-deficient BIO14.6 hamsters, are largely prevented by dominant-negative inhibition of a 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 markedly reduced by inhibition of endogenous TRPV2 in a dominant-negative manner. Furthermore, histological, biochemical and physiological indices characterizing dystrophic pathology, such as increased number of central nuclei and fiber size variability/fibrosis/apoptosis, elevated creatine kinase level in serum and reduced muscle performance, were all ameliorated in the mdx/Tg mice. Similar beneficial effects were also observed in muscles of BIO14.6 hamsters infected with adenovirus carrying mutant TRPV2. We propose that TRPV2 is a principal Ca^<2+>-entry route leading to sustained [Ca^<2+>]_i increase and muscle degeneration, and is a promising therapeutic target for treatment of muscular dystrophy.