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17 Modulating Skeletal Muscle Hypertrophy and Atrophy: Signaling Pathways and Therapeutic Targets

David J. Glass, George D. Yancopoulos


The skeletal muscles of adult animals are continuously shaped by forces and conditions that regulate size, composition, and strength. Weight-bearing exercise, as well as agents such as insulin-like growth factor-1 (IGF-1) and anabolic steroids, can promote muscle growth. On the other hand, the lack of exercise, nerve injuries, or glucocorticoids can cause muscle wasting, which is also associated with diseases such as cancer, AIDS, and sepsis. Although the growth of other biologic structures can involve increases in the number of cells composing that structure, as well as increases in the size of individual cells, the size of adult skeletal muscles is primarily regulated by modulating cell size as opposed to cell number. Muscles are composed of longitudinal groupings of many individual muscle fibers, with each myofiber corresponding to an elongated and multinucleated single cell, and it is the modulation of the diameters of these individual myofibers that results in changes in the size of adult muscles. Hypertrophy refers to increases in the diameter of individual myofibers, as well as to the corresponding increases in the girth of entire muscles, and atrophy refers to reciprocal decreases in size. Muscle hypertrophy is a natural adaptive response to load-bearing exercise and is associated with an enhanced rate of protein synthesis (Goldspink et al. 1983). This increase in protein synthesis allows new contractile filaments to be added to the preexisting muscle fiber, which in turn results in increased size and also enables the muscle to generate greater force.

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