Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

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J Appl Physiol. 2007 Mar;102(3):1143-51.

Effect of denervation on mitochondrially mediated apoptosis in

skeletal muscle.

Adhihetty PJ, O'leary MF, Chabi B, Wicks KL, Hood DA.

School of Kinesiology and Health Science, York Univ., Toronto, ON,

Canada M3J 1P3.

Chronic muscle disuse induced by denervation reduces mitochondrial

content and produces muscle atrophy. To investigate the molecular

mechanisms responsible for these adaptations, we assessed 1)

mitochondrial biogenesis- and apoptosis-related proteins and 2)

apoptotic susceptibility and cell death following denervation.

Rats were subjected to 5, 7, 14, 21, or 42 days of unilateral

denervation of the sciatic or peroneal nerve. Muscle mass and

mitochondrial content were reduced by 40-65% after 21 and 42 days of

denervation.

Denervation-induced decrements in mitochondrial content occurred

along with 60% and 70% reductions in transcription factor A (Tfam)

and peroxisome proliferator-activated receptor-gamma coactivator

(PGC)-1alpha, respectively. After 42 days of denervation, Bax was

elevated by 115% and Bcl-2 was decreased by 89%, producing a 16-fold

increase in the Bax-to-Bcl-2 ratio.

Mitochondrial reactive oxygen species production was markedly

elevated by 5- to 7.5-fold in subsarcolemmal mitochondria after 7,

14, and 21 days of denervation, whereas reactive oxygen species

production in intermyofibrillar (IMF) mitochondria was reduced by 40-

50%. Subsarcolemmal and IMF mitochondrial levels of MnSOD were also

reduced by 40-50% after 14-21 days of denervation. The maximal rate

of IMF mitochondrial pore opening (V(max)) was elevated by 25-35%,

and time to V(max) was reduced by 20-25% after 14 and 21 days,

indicating increased apoptotic susceptibility. Myonuclear decay,

assessed by DNA fragmentation, was elevated at 7-21 days of

denervation.

Our data indicate that PGC-1alpha and Tfam are important factors

that likely contribute to the reduced mitochondrial content after

chronic disuse.

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.