Elevated skeletal muscle apoptotic signaling following glutathione depletion |
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Authors: | Aaron D Dam Andrew S Mitchell James W E Rush Joe Quadrilatero |
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Institution: | (1) Department of Kinesiology, University of Waterloo, Waterloo, ON, N2L3G1, Canada; |
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Abstract: | Oxidative stress has a well-established role in numerous intracellular signaling pathways, including apoptosis. Glutathione
is an important cellular antioxidant and is the most abundant low molecular weight thiol in the cell. Although previous work
has shown a link between glutathione and apoptosis, this relationship has not been defined in skeletal muscle. The present
investigation examined the effect of glutathione depletion on skeletal muscle apoptotic signaling, and mitochondrial apoptotic-susceptibility.
Administration of l-buthionine-S,R]-sulfoximine (BSO; 30 mM in drinking water for 10 days) caused glutathione depletion in whole muscle and
isolated mitochondria, as well as elevated muscle catalase protein content and reactive oxygen species (ROS) generation. Glutathione
depletion was associated with elevated DNA fragmentation, mitochondrial Bax levels, Poly(ADP-ribose) polymerase (PARP) cleavage,
and calpain activity; however, caspase-3, -8, and -9 activity were not altered. BSO administration was also associated with
higher cytosolic and nuclear protein levels of apoptosis-inducing factor (AIF), but not cytochrome c, second mitochondria-derived
activator of caspase (Smac), or endonuclease G (EndoG). In addition, isolated mitochondria from BSO animals demonstrated significantly
lower membrane potential, increased Ca2+-induced permeability transition pore opening, and greater basal and ROS-induced AIF and cytochrome c release. These results
demonstrate that glutathione depletion in skeletal muscle increases caspase-independent signaling, as well as augments mitochondrial-associated
apoptotic events to subsequent cell death stimuli. |
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