CLINICAL SCIENCES: Symposium: Contraction-Induced Muscle Hypertrophy and Injury Run Amok
Skeletal muscle has an amazing capacity to adapt to the functional demands placed on it. The specific adaptation depends in large part on the type of activity. Activities requiring high force will increase maximal force output, whereas activities requiring sustained power output will improve muscle’s ability to dispose of glucose and oxidize fatty acids. Increased muscle activity is often accompanied by contraction-induced injury. In healthy muscle, the damage is repaired rapidly, and the remodeled muscle becomes healthier as evidenced by a reduced susceptibility to injury, an increased ability to generate force, and a greater capacity for sustaining high rates of ATP production (Fig. 1). In some situations, however, muscle activity and the associated injury may push diseased or severely deconditioned muscle to the limits of its capacity for adaptation. The muscle attempts to repair itself and adapt, but continued use may ultimately lead to muscle wasting.
Muscle regrowth following a period of inactivity provides an example in which muscle adaptation to increased use may be limited. Inactivity results in rapid muscle atrophy (1,4). Returning to normal activity results in contraction-induced injury followed by muscle regrowth (7,8,16). Unfortunately, clinical studies show that muscle size and strength often do not recover completely after a period of inactivity despite extensive rehabilitation (5,10). This may be especially true for muscles at either end of the life span. For example, unloading muscles during the postnatal growth period causes a reduction in mass that is not fully reversed after the muscle is reloaded (9). Similarly, when muscles from old animals are reloaded after a period of inactivity, mass recovery is significantly less than in younger animals (17). The inability to recover fully from a period of inactivity suggests an impaired adaptive response.
Duchenne muscular dystrophy (DMD) is another example in which the adaptive response may be limited. DMD is an inherited, X-linked recessive disease caused by mutations in the dystrophin gene. Boys with DMD are normal at birth, but between the ages of 3 and 5 yr begin having difficulty with activities that require strength. After an initial period in which the limb muscles become noticeably enlarged, patients become progressively weaker. Most boys with DMD are confined to a wheelchair by adolescence and typically die of respiratory failure before the age of 30. Physical activity is thought to exacerbate DMD because dystrophin-deficient fibers are more susceptible to contraction-induced injury (2,12). Histological examination of muscle from DMD patients in an early stage of the disease shows groups of necrotic fibers as well as very large and very small fibers. These observations suggest that dystrophic muscle fibers are in various stages of degeneration, regeneration, and hypertrophy. As the disease progresses, significant fiber loss occurs, and connective tissue replaces muscle fibers, suggesting a limit to the adaptive response.
The mechanisms underlying muscle adaptation to increased levels of physical activity remain obscure but likely involve interactions among intrinsic and extrinsic factors. A critical factor intrinsic to muscle is the intracellular pathways that mediate responses to chemical and mechanical signals. Scattered evidence shows that contractile activity activates several different signaling pathways, but many details are still lacking (13). Even less is known about the role extrinsic factors play in muscle adaptation. One such factor is the immune system. Contraction-induced injury causes resident and invading immune cells to secrete substances believed to regulate the recruitment and behavior of other immune cells, as well as various aspects of muscle repair (11,15). The intensity and duration of the immune response may affect the ability of muscle to adapt to increased use. For example, the blunted immune response to exercise in the elderly (3,6) may affect their ability to recover completely from periods of inactivity, whereas the persistent intramuscular immune response in DMD patients may impair muscle regeneration and promote muscle wasting (14).
A symposium presented at the 2002 Annual Meeting of the American College of Sports Medicine addressed various aspects of limited muscle adaptation. The two papers following this introduction are the result of that symposium. In the first paper, Drs. Gosselin and McCormick outline cellular and functional changes in the dystrophic diaphragm and examine the effect of suppressing the immune system on dystrophic diaphragm function. In the second paper, Drs. Machida and Booth review cellular changes that occur in muscle during periods of inactivity and recovery from inactivity, and propose signaling pathways that may be involved. These two papers will help the reader have a better understanding of cellular and immunological mechanisms that may be involved in limiting the adaptive response to increased use.
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