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

Abstract

Apoptosis is well accepted as a type of cell death occurring in the development of mammalian muscles, but the death of adult myofibres in neuromuscular disorders and exercise-induced muscle damage is usually explained in terms of muscle necrosis. The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibres of mdx mouse has been well substantiated. 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-course analysis has been performed in adult C57BL/6 mice. Groups of five mice were 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 and by electrophoretic detection of fragmented DNA; the expression of Bcl-2, Bax, Fas, ICE, p53 and ubiquitin was examined by immunohistochemistry and Western blot. Absent in muscles of normal 'sedentary' mice, apoptotic myonuclei peak in muscles of normal mice after a night of spontaneous wheel-running (4% +/- 3.5, immediately and 2.5% +/- 1.8 after 6 h rest, P < 0.05 vs non-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 content of Bcl-2 decreases whereas Bax, Fas, ICE and ubiquitin modify their pattern of expression in correlation with the changes in apoptotic myonuclei. Apoptosis of endothelial cells is present after the night of wheel-running 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 number of apoptotic nuclei in adult muscle fibres and in endothelial cells. It remains to be established whether muscle apoptosis is restricted to the repair mechanisms, as often suggested in many pathologic processes, or it is also part of pathogenesis of muscle damage. Regardless of whether these results are extended to human dystrophies, the clinical implications in terms of secondary pathogenetic mechanisms and muscle training are obvious.

Activation of the erythropoietin receptor in human skeletal muscle

“…Another alternative process for EPOR activation in skeletal muscle is protection against apoptosis induced by reversible ischemia by activation of the antiapoptotic factors Bcl-2 and Bcl-XL (3)(4)(5). However, expression changes of these factors are demonstrated to occur days after repetitive exercise bouts (38). All together the present study encourages further elaborating of EPOR regulated gene expression in the human skeletal muscle.…”

Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C–deficient mice

“…Second, lamina disruption and heterochromatin clumping have been described as early features of apoptosis (46,47). Third, exercise-induced apoptosis has been demonstrated in dystrophin-deficient skeletal muscle (48). Finally, apoptosis has been implicated in disease progression in DCM and in cardiac conduction disorders (49)(50)(51).…”

Cell death, clearance and immunity in the skeletal muscle

“…26 During intense exercise, on-going cell death and DNA fragmentation together with undamaged sarcolemma and preserved contractile proteins are detectable in the muscle. 27,28 Necrosis-released enzymes are found in human blood after eccentric muscular contractions as those performed during marathon, weight-bearing exercises and downhill running. 29,30 Serum CK might not only reflect fiber disruption.…”