Stimulation of slow skeletal muscle fiber gene expression by calcineurin in vivo

Adult skeletal muscle fibers can be categorized into fast and slow twitch s ubtypes based on specialized contractile and metabolic properties and on di stinctive patterns of muscle gene expression. Muscle fiber-type characteris tics are dependent on the frequency of motor nerve stimulation and are thou ght to be controlled by calcium-dependent signaling. The calcium, calmoduli n-dependent protein phosphatase, calcineurin, stimulates slow fiber-specifi c gene promoters in cultured skeletal muscle cells, and the calcineurin inh ibitor, cyclosporin A inhibits slow fiber gene expression in vivo, suggesti ng a key role of calcineurin in activation of the slow muscle fiber phenoty pe, Calcineurin has also been shown to induce hypertrophy of cardiac muscle and to mediate the hypertrophic effects of insulin-like growth factor-1 on skeletal myocytes in vitro. To determine whether activated calcineurin was sufficient to induce slow fiber gene expression and hypertrophy in adult s keletal muscle in vivo, we created transgenic mice that expressed activated calcineurin under control of the muscle creatine kinase enhancer. These mi ce exhibited an increase in slow muscle fibers, but no evidence for skeleta l muscle hypertrophy, These results demonstrate that calcineurin activation is sufficient to induce the slow fiber gene regulatory program in vivo and suggest that additional signals are required for skeletal muscle hypertrop hy.