Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

• Published in: Journal of applied physiology (1985) Vol. 102; no. 3; pp. 1143 - 1151
• Main Authors: Adhihetty, Peter J, O'Leary, Michael F. N, Chabi, Beatrice, Wicks, Karen L, Hood, David A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Physiological Soc 01-03-2007; American Physiological Society
• Subjects: Adaptation, Physiological; Animals; Apoptosis; Apoptosis - physiology; Biological and medical sciences; Cell Nucleus - metabolism; Cell Respiration - physiology; Chronic illnesses; Fundamental and applied biological sciences. Psychology; Gene Expression; Human health and pathology; In Situ Nick-End Labeling; Life Sciences; Male; Medical disorders; Mitochondria, Muscle - physiology; Mitochondrial DNA; Muscle Denervation; Muscle Fibers, Skeletal - pathology; Muscle Proteins - metabolism; Muscle, Skeletal - innervation; Muscle, Skeletal - pathology; Muscle, Skeletal - physiology; Muscular Atrophy - pathology; Muscular Disorders, Atrophic - pathology; Muscular Disorders, Atrophic - physiopathology; Musculoskeletal system; Neurons; Proteins; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Superoxide Dismutase - metabolism; Tissues and Organs; Voltage-Dependent Anion Channels - metabolism; Reactive oxygen species; peroxisome proliferator-activated receptor-γ coactivator-1α; Striated muscle; PPAR-γ receptor; mitochondrial biogenesis; mitochondrial respiration; Vertebrata; Mitochondria; Mammalia; muscle disuse; Respiration; Apoptosis; Denervation; receptor-gamma coactivator-1 alpha; peroxisome proliferator-activated; reactive oxygen species
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00768.2006

1 School of Kinesiology and Health Science and 2 Department of Biology, York University, Toronto, Ontario, Canada
Submitted 11 July 2006
; accepted in final form 14 November 2006
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- coactivator (PGC)-1 , 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-1 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.
mitochondrial biogenesis; muscle disuse; reactive oxygen species; mitochondrial respiration; peroxisome proliferator-activated receptor- coactivator-1
Address for reprint requests and other correspondence: D. A. Hood, School of Kinesiology and Health Science, York Univ., Toronto, ON, Canada M3J 1P3 (e-mail: dhood{at}yorku.ca )