J.G. Tidball, H.X. Nguyen, M.J. Spencer

Loss of muscle mass (sarcopenia) is a predictable occurrence during aging that reduces the quality of life, and can contribute to functional defects in other systems that are associated with reduced physical activity. Mechanical loading of muscle can slow sarcopenia, but the mechanisms through which the mechanical environment can influence muscle mass are not well-understood. Our current work is directed toward examining the role of neuronal nitric oxide synthase (nNOS) as a mechanical signal transducer that functions as a positive regulator of muscle mass. Our recent findings have shown that increased muscle loading increases the expression and activity of nNOS, and that NO can reduce the activity of calcium-dependent proteases in muscle by S-nitrosylation of cysteine at the active site of calpain proteases. We have tested whether sarcopenia that occurs during muscle unloading can result from a reduction of NO-mediated inhibition of calpain activity by generating transgenic mice in which there is a muscle specific over-expression of either nNOS, or the endogenous inhibitor of calpains, called calpastatin. Expression of either transgene significantly reduces the rate of muscle mass loss during muscle unloading. Because there is a decline in the concentration of nNOS in muscle during aging, and physical activity is reduced during aging, some of the sarcopenia that occurs during aging may result from a reduction of NO-mediated inhibition of calpain activity in muscle. (Supported by the National Institutes of Health and by NASA).

Keywords (Optional): 
nitric oxide