1 Mariannick Marcil, Karine Bourduas, Alexis Ascah, Yan Burelle ...

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ABSTRACT The purpose of this study was to determine if regular exercise (treadmill running, 10 weeks) alters the susceptibility of rat isolated heart mitochondria to Ca 2+ -induced PTP opening and if this could be associated with changes in the modulation of PTP opening by selected physiological effectors. Basal leak-driven and ADP-stimulated respiration in the presence of substrates for complex I, II and IV were not affected by training. Fluorimetric studies revealed that in the control (C) and exercise-trained (T) groups, the amount of Ca 2+ required to trigger PTP opening was greater in the presence of complex II vs I substrates (230 ± 12 vs 134 ± 7 nmol Ca 2+ .mg prot. -1 respectively, P < 0.01, pooled average of C and T groups). In addition, with a substrate feeding the complex II, training increased by 45 % (P < 0.01) the amount of Ca 2+ required to trigger PTP opening, both in the presence and absence of the PTP inhibitor cyclosporin A. However, , ROS production, NAD(P)H ratio and Ca 2+ uptake kinetics were not different in mitochondria from both groups. Taken together, these results suggest the existence of a substrate-specific regulation of the PTP in heart mitochondria and that regular exercise results in a reduced sensitivity to Ca 2+ -induced PTP opening in presence of complex II substrates. Key words: Exercise, heart, mitochondrial function, Ca 2+ stress 2
INTRODUCTION Mitochondria play a pivotal role in controlling cell death through their capacity to trigger both necrosis and apoptosis (16, 18, 25, 39). A number of studies have shown that an increased permeability of the mitochondrial membranes is a key event in these processes (37, 41, 59). Although several mechanisms of membrane permeation have been suggested, one of the best documented involves the opening of the permeability transition pore (PTP). The mPTP is a high conductance non-specific pore presumably formed by a supramolecular complex spanning the double membrane system of the mitochondria mainly at contact sites. Although it is increasingly recognized the molecular composition of the mPTP is probably variable (61), the prevailing hypothesis is that it includes the adenylate translocator (ANT), the porin pore (VDAC) and the matrix protein foldase cyclophilin-D. Opening of the PTP induces the loss of mitochondrial membrane potential ( ), uncoupling of oxidative phosphorylation, high amplitude swelling of the matrix and the release of several pro-apoptotic factors that are normally sequestered in mitochondria such as cytochrome c, AIF, Smac/Diablo, endonuclease G and Omi/HtrA2 (5, 25). In the heart, PTP opening was shown to occur during reperfusion following ischemia and to be involved in contractile dysfunction and tissue injury (19, 23, 24, 31, 32, 35). This phenomenon can be explained by the fact that many of the conditions required to open the PTP in vitro prevail in cardiac cells early during reperfusion. On the other hand, ischemic pre- conditioning was shown to decrease the sensitivity to PTP opening in isolated mitochondria (1) and intact cardiomyocytes (28) and perfused hearts (27, 31). However whether exercise training, another physiological stress capable of inducing a cardio-protective phenotype (9, 14, 42, 51), can beneficially alter the regulatory properties of the PTP remains largely unknown. 3
Page 1: Articles in PresS. Am J Physiol Hea
Page 5 and 6: METHODS Animal care All experiments
Page 7 and 8: asal respiration due to the presenc
Page 9 and 10: Mitochondrial Adenylate Content End
Page 11 and 12: increase in CRC which was not stati
Page 13 and 14: otenone. No significant differences
Page 15 and 16: assessed. Sordahl et al. (56) repor
Page 17 and 18: production (12, 26) as well as an a
Page 19 and 20: REFERENCES 1. Argaud L, Gateau-Roes
Page 21 and 22: 38. Kowaltowski AJ, Vercesi AE, and
Page 23 and 24: AKNOWLEDGEMENTS This work was suppo
Page 25 and 26: Table 2: Effect of exercise on mito
Page 27 and 28: Glut/mal Rotenone Antimycin A Oligo
Page 29 and 30: Ca2+ retention capacity (nmol.mg -1
Page 31 and 32: Fluorescence (A.U.) Fluorescence (A
Page 33 and 34: FIGURE LEGENDS Figure 1: Overview o

1 Mariannick Marcil, Karine Bourduas, Alexis Ascah, Yan Burelle ...

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