Mechanisms regulating muscle wasting during muscle disuse or aging
J.G. Tidball, H.X. Nguyen, M.J. Spencer
Departments of Physiological Science, and Pathology and Laboratory Medicine. Univ. of California, Los Angeles 90095, USA
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).
Key words:
muscle; nitric oxide; calpain; sarcopenia
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