Journal of Applied Physiology
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J Appl Physiol (November 22, 2006). doi:10.1152/japplphysiol.00768.2006
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Submitted on July 11, 2006
Accepted on November 14, 2006

Effect of denervation on mitochondrially-mediated apoptosis in skeletal muscle

Peter J Adhihetty1, Michael F.N. O'Leary2, Beatrice Chabi1, Karen L Wicks2, and David A Hood3*

1 Biology, York University, Toronto, Canada
2 Kinesiology and Health Science, York University, Toronto, Canada
3 Biology, York University, Toronto, Canada; Kinesiology and Health Science, York University, Toronto, Canada

* To whom correspondence should be addressed. E-mail: dhood{at}yorku.ca.

Chronic muscle disuse induced by denervation causes a reduction in mitochondrial content and produces atrophy. To investigate the mechanisms responsible for these adaptations, we assessed 1) mitochondrial biogenesis and apoptosis-related proteins and 2) apoptotic susceptibility and cell death following denervation. Rats underwent unilateral denervation (DEN) of either the sciatic or peroneal nerve for 5, 7, 14, 21, or 42 days. Muscle mass and mitochondrial content were reduced by 40-65% following denervation of 21d and 42d. DEN-induced decrements in mitochondrial content occurred coincident with 60% and 70% reductions in Tfam and PGC-1{alpha}, respectively. Following 42d of DEN, BAX was elevated by 115% while Bcl-2 decreased 89%, producing a 16-fold increase in the BAX:Bcl-2 ratio. Mitochondrial ROS production was markedly elevated by 5-7.5-fold in SS mitochondria following 7, 14, and 21 days of DEN, while ROS production in IMF mitochondria was reduced by 40-50%. SS and IMF mitochondrial levels of MnSOD were also reduced by 40-50% following 14-21d of DEN. The maximal rate of IMF mitochondrial pore opening (Vmax) was elevated by 25-35% and time to Vmax was reduced by 20-25% following 14d and 21d, indicating increased apoptotic susceptibility. Myonuclear decay, assessed by DNA fragmentation, was elevated between 7-21d of denervation. Our data indicate PGC-1{alpha} and Tfam are important factors which contribute to the reduced mitochondrial content following denervation. In addition, our results illustrate that, despite the reduced mitochondrial content, denervated muscle has greater mitochondrial apoptotic susceptibility which coincided with elevated apoptosis, and these processes may contribute to denervation-induced muscle atrophy.




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