Apoptosis en el musculo esqueletico con el envejecimiento

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Apoptosis in skeletal muscle with aging
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.
Apoptosis in skeletal muscle withaging. Am J Physiol Regulatory
Integrative Comp Physiol 282: R519–R527, 2002. First published
October 18, 2001; 10.1152/ajpregu.00458.2001.—Sarcopenia
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 344rats. Apoptosis (mono- and oligonucleosome fragmentation)
in the gastrocnemius muscle was increased by
50% in the old rats compared with the adult animals. Furthermore,
there was a significant correlation between cytosolic
cytochrome c and caspase-3 activity, although neither
cytochrome c nor caspase-3 activity increased significantly
with age. Furthermore, there was a significant correlationbetween 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 demonstrated
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 inapoptosis 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 decrease
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). Alternatively,
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 mitotictissues, such as liver and
white blood cells, which serve to prevent age-associated
tumorigenesis and to maintain overall control of
immunocompetent cells, respectively (24, 25). However,
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 pathophysiological
and certain physiologicalconditions, there is sufficient evidence to demonstrate that apoptosis
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), skeletal
muscle denervation (8), muscle unweighting (3),
and during acute exercise (38). With normal aging,
there are several reports that indicate a loss in fiber
number (4,30), but only one report investigated apoptosis
in skeletal muscle showing that the rhabdosphincter
muscle cells of aged humans may be partly
lost by apoptosis (43).
Although apoptosis may occur via several mechanisms,
mitochondria have recently been implicated
as major regulatory centers for apoptosis (11, 20, 21).
It has been suggested that internal cellular stimuli,
such as high levelsof calcium or reactive oxygen
intermediates, may trigger apoptosis by the cytochrome
c-dependent pathway (15, 16, 35, 39). Other
pathways require an alternate upstream activator(s) to
initiate the caspase cascade (cysteine-dependent, aspartate-
specific proteases, i.e., caspase-8 and caspase-
10). For example, binding of tumor necrosis factor
(TNF)-_ to its receptor can induce apoptosis in...
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