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1 Kinesiology and Health Science and Biology, York University, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: dhood{at}yorku.ca.
Apoptosis can be evoked by ROS-induced mitochondrial release of the pro-apoptotic factors cytochrome c and apoptosis inducing factor (AIF). Since skeletal muscle is composed of two mitochondrial subfractions that reside in distinct subcellular regions, we investigated the apoptotic susceptibility of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. SS and IMF mitochondria exhibited a dose-dependent release of protein in response to H2O2 (0, 25, 50, 100µM). However, IMF mitochondria were more sensitive to H2O2 and released a 2.5-fold and 10-fold greater amount of cytochrome c and AIF, respectively, compared to SS mitochondria. This coincided with a 44% (P < 0.05) greater rate of opening (Vmax) of the protein release channel, the mitochondrial transition pore (mtPTP), in IMF mitochondria. IMF mitochondria also exhibited a 47% (P < 0.05) and 60% (0.05<P<0.1) greater expression of key mtPTP components, VDAC and cyclophilin D, respectively, along with a 3-fold greater cytochrome c content, but similar levels of AIF compared to SS mitochondria. Despite a lower susceptibility to H2O2-induced release, SS mitochondria possessed a 10-fold greater Bax-to-Bcl-2 ratio (P <0.05), a 2.7-fold greater rate of ROS production, and an approximate 2-fold greater membrane potential than IMF mitochondria. The expression of the anti-oxidant enzyme, MnSOD, was similar between subfractions. Thus, the divergent protein composition and function of the mtPTP between SS and IMF mitochondria contributes to a differential release of cytochrome c and AIF in response to ROS. Given the relatively high proportion of IMF mitochondria within a muscle fiber, this subfraction is likely most important in inducing apoptosis when presented with apoptotic stimuli, ultimately leading to myonuclear decay and muscle fiber atrophy.
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