ABSTRACT
Apoptosis results in DNA fragmentation and subsequently destruction of cells containing a single nucleus. Multi-nucleated cells such as skeletal muscle fi bers can encounter apoptotic-induced loss of single nuclei (nuclear apoptosis) without destruction of the entire fi ber. Th e loss of nuclei contributes to skeletal muscle atrophy and aging-associated loss of skeletal muscle. Muscle satellite cells are myogenic stem cells that are critically important for maintenance of normal muscle mass and also in muscle growth and hypertrophy. However, satellite cells appear to be targeted by apoptosis, particularly in conditions of disuse and aging. Muscle loss in aging (sarcopenia), disuse and denervation are all associated with elevated apoptosis. Apoptotic signaling in skeletal muscle occurs via three general pathways. Mitochondria-associated caspase signaling occurs when Bax-regulated increases in mitochondria permeability result in release of cytochrome c from the mitochondria, which in turn, forms an apoptosome, cleaving and activating caspase-9 and subsequently caspase-3. Mitochondrial permeability also increases release of AIF, EndoG and Smac/DIABLO which in turn activates apoptosis in
a non-caspase dependent signaling mechanism. Aging is also associated with increased cytokine dependent death receptor activation apoptosis in skeletal muscle. While acute exhaustive exercise is associated with increased apoptosis, adaptations to more moderate exercise and caloric restriction improve apoptotic signaling in muscles of old animals or humans, but do not markedly alter apoptotic processes in muscles of young animals or humans. Understanding how the stresses (e.g., oxidative stress and infl ammation), might trigger apoptosis will lead us to develop better therapeutic interventions which are designed to improve muscle maintenance and reduce loss of muscle under wasting and diseased conditions.
