| Skeletal muscle is an adaptable tissue which responds to both increases and decreases in contractile activity. Decreases in contractile activity, invoked by denervation, result in a dramatic reduction in muscle mass (3), and in performance capabilities (133). These changes in the characteristics of skeletal muscle are brought about, at least in part, by an elevation in the rate of protein degradation (93, 94), and by an increase in the incidence of programmed cell death (apoptosis) (3). In contrast, skeletal muscle increases its oxidative capacity and its endurance performance in response to repeated bouts of contractile activity. In particular, chronic contractile activity induces an increase in total mitochondrial content (57), and in the expression of anti-apoptosic factors (1). Thus, the plasticity of skeletal muscle enables this tissue to adjust its composition in response to changes in contractile activity.; Sarcopenia is a muscular condition that is characterized by the age-associated loss of skeletal muscle mass and strength. Typically this condition begins in the fourth to fifth decade of human life, and it often leads to a significant decrease in an individual's quality of life (33). Furthermore, it is estimated that by the year 2030 the elderly population will rise from 13% to 20%, and that the health care-related cost of treating these individuals will reach 130 billion dollars (84). Thus, there is a significant demand for developing affordable treatments that reduce the damaging consequences of sarcopenia. To date, chronic physical activity represents one of the more promising treatments that can attenuate the age-associated loss in muscle mass and strength. However, many questions still exist surrounding the exact molecular mechanisms by which contractile activity of skeletal muscle reduces muscle atrophy. Thus, in the present study we evaluated how prior chronic stimulation affects mitochondrial function and apoptosis in denervated muscle. In comparison to sham-operated control, denervation resulted in a reduction in total mitochondrial content that was primarily attributable to a decrease in subsarcolemmal (SS) mitochondrial yield. Prior chronic stimulation prevented the decrease in the SS subfraction and retained total mitochondrial content at sham-operated control levels. Moreover, chronic denervation increased the apoptotic susceptibility of skeletal muscle by elevating the Bax:Bcl-2 ratio, and by increasing the production of reactive oxygen species (ROS). The expression of the anti-oxidant protein manganese superoxide dismutase (MnSOD) was also decreased in response to denervation. These changes in muscle apoptotic susceptibility were not prevented by prior chronic stimulation. In addition, we also measured a denervation-induced increase in the expression of Beclin-1, which is a protein that is essential to autophagic cell death. Thus, prior chronic stimulation of skeletal muscle, at the intensity, duration and frequency as applied here, does not prevent the apoptotic adaptations which occur as a result of denervation. However, prior chronic stimulation may prevent some of the denervation-induced apoptosis by increasing the expression of anti-apoptotic factors, and by maintaining mitochondrial content at a higher level than typically found in denervated muscle. |
