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Unformatted text preview: Apoptosis in skeletal muscle with aging AMIE DIRKS AND CHRISTIAAN LEEUWENBURGH University of Florida, Biochemistry of Aging Laboratory, College of Health and Human Performance, Center for Exercise Science, College of Medicine, Gainesville, Florida 32611 Received 1 August 2001; accepted in final form 18 October 2001 Dirks, Amie, and Christiaan Leeuwenburgh. Apopto- sis in skeletal muscle with aging. Am J Physiol Regulatory Integrative Comp Physiol 282: R519R527, 2002. First pub- lished October 18, 2001; 10.1152/ajpregu.00458.2001.Sar- copenia may be partly due to a loss in total fiber number by apoptosis. We have investigated age-related alterations in the mitochondria-mediated pathway leading to apoptosis in the gastrocnemius muscle from 6-mo-old and 24-mo-old male Fisher 344 rats. Apoptosis (mono- and oligonucleosome frag- mentation) in the gastrocnemius muscle was increased by 50% in the old rats compared with the adult animals. Fur- thermore, there was a significant correlation between cyto- solic cytochrome c and caspase-3 activity, although neither cytochrome c nor caspase-3 activity increased significantly with age. Furthermore, there was a significant correlation between caspase-3 activity and mono- and oligonucleosome fragmentation in the old rats only. Mitochondrial Bcl-2 and Bax were not altered with age. In vitro experiments demon- strated that activation of the caspase cascade in skeletal muscle might be limited by procaspase-9 activation. This is the first study to explore the role of apoptosis in sarcopenia and suggests that subtle changes in apoptosis are involved. free radicals; oxidative stress; apoptotic protease activating factor-1; Bcl-2 family; cytochrome c ; caspases; mitochondria SKELETAL MUSCLE MASS decreases with age, via a de- crease in fiber number and atrophy of the remaining muscle fibers, by largely unidentified mechanisms (26, 32). One potential mechanism of atrophy originates from proteolytic pathways (13, 18, 23). In addition, other mechanisms, including neurological mechanisms (loss in motor neurons) and hormonal changes with age, are likely to contribute to muscle loss (37). Alter- natively, the loss of muscle mass due to apoptosis with normal aging may play an important role, but it has not been well investigated. Accelerated apoptosis with normal aging has been reported in several mitotic tissues, such as liver and white blood cells, which serve to prevent age-associ- ated tumorigenesis and to maintain overall control of immunocompetent cells, respectively (24, 25). How- ever, it is still controversial whether apoptosis occurs in postmitotic tissues with normal aging, such as brain, heart, and skeletal muscle (24, 27, 34, 45). With patho- physiological and certain physiological conditions, there is sufficient evidence to demonstrate that apop- tosis plays a key role in skeletal muscle cell loss. For example, apoptosis has been documented to occur in muscular dystrophy (38), chronic heart failure (2), skel-...
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