Involvement of TRPC3-Nox2 complex formation in the progression of striated muscle atrophy

<p>Striated muscles, including cardiac muscle and red skeletal muscle which abundantly express myoglobin, play a crucial role not only in systemic motor function but also in the homeostasis of energy metabolism. The muscle atrophy that comes with age and disease will reduce systemic function. We have previously shown that the onset and progression of myocardial atrophy induced by the anticancer drug doxorubicin are mediated through the functional interactions between transient receptor potential canonical (TRPC) 3 protein and the ROS-producing NADPH oxidase 2 (Nox2), which is responsible for ROS production, on the cardiac myocyte membrane. We also identified ibudilast, a bronchodilator, can inhibit TRPC3-Nox2 complex formation and reduced the systemic muscle weight loss induced by doxorubicin. In this study, we investigated whether TRPC3/Nox2 complex formation is a therapeutic target for skeletal muscle atrophy in muscular dystrophy. In the skeletal muscle of Duchenne muscular dystrophy (mdx) model mice, TRPC3-Nox2 protein complex formation was markedly observed, and pharmacological inhibition of this complex formation by ibudilast attenuated skeletal muscle atrophy and motor functional loss in mdx mice. Furthermore, administration of pyrazole-3 (Pyr3), a TRPC3-selective inhibitor, to mdx mice similarly attenuated muscle atrophy and weakness. Oxidative stress caused in atrophied muscle cells was also suppressed by preventing TRPC3-Nox2 interaction. These results suggest that TRPC3-Nox2 complex formation may be a new therapeutic target for preventing myopathic muscle atrophy.</p>