Apoptosis of myofibres and satellite cells: exercise-induced damage in skeletal muscle of the mouse

Apoptosis is well accepted as a type of cell death occurring in the develop ment of mammalian muscles, but the death of adult myofibres in neuromuscula r disorders and exercise-induced muscle damage is usually explained in term s of muscle necrosis. The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibres of mds mouse has been well subs tantiated. Moreover, apoptotic myonuclei have been reported to increase in mdx mice 2 days after spontaneous exercise, To investigate the contribution of apoptosis to exercise-induced damage of normal muscle fibre a time-cour se analysis has been performed in adult C57BL/6 mice. Groups of five mice w ere sacrificed immediately after the end of the exercise, and after a rest period of 6 or 96 h. The amount of apoptosis in leg muscles was assessed by electron microscopy, by the terminal deoxynucleotidyl transferase assay an d by electrophoretic detection of fragmented DNA; the expression of Bcl-2, Bar, Fas, ICE, p53 and ubiquitin was examined by immunohistochemistry and W estern blot. Absent in muscles of normal 'sedentary' mice, apoptotic myonuc lei peak in muscles of normal mice after a night of spontaneous wheel-runni ng (4% +/- 3.5, immediately and 2.5% +/- 1.8 after 6 h rest, P < 0.05 vs no n-runner mice); they then decrease but are present 4 days later (0.8% +/- 1 .5). Satellite cells are also involved in the apoptotic process. Myofibre c ontent of Bcl-2 decreases whereas Bar, Fas, ICE and ubiquitin modify their pattern of expression in correlation with the changes in apoptotic myonucle i. Apoptosis of endothelial cells is present after the night of wheel-runni ng and with a twofold increase 4 days later (1.5 +/- 2.3 and 4.8 +/- 4.4: P < 0.05, respectively). Satellite cells are also involved in the apoptotic process. Thus, spontaneous running in unaccustomed mice increases the numbe r of apoptotic nuclei in adult muscle fibres and in endothelial cells. It r emains to be established whether muscle apoptosis is restricted to the repa ir mechanisms, as often suggested in many pathologic processes, or it is al so part of pathogenesis of muscle damage. Regardless of whether these resul ts are extended to human dystrophies, the clinical implications in terms of secondary pathogenetic mechanisms and muscle training are obvious.