Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle.
Skeletal muscle is highly adaptable in response to increases and decreases in contractile activity. The purpose of this study was to determine whether the preconditioning of skeletal muscle has a protective effect against subsequent denervation-induced apoptotic protein expression. To investigate this, we chronically stimulated the tibialis anterior and extensor digitorum longus muscles for 7 days (10 Hz, 3 h/day) before 7 days of denervation. Denervation reduced total cytochrome-c oxidase activity by 39%, which was likely a consequence of a decrease in subsarcolemmal (SS) mitochondria. This decrease in the SS subfraction was prevented by prior chronic stimulation and, as a result, maintained total mitochondrial content at control levels. The expression of Bax was elevated 2.2-fold by denervation, and prior chronic stimulation did not attenuate this increase. This produced a increase in the Bax-to-Bcl-2 ratio, indicating greater muscle apoptotic susceptibility. Denervation also decreased state 3 respiration in SS and intermyofibrillar mitochondria and elevated state 4 reactive oxygen species production within both mitochondrial subfractions. These changes were not prevented by prior chronic stimulation. Furthermore, the antioxidant protein MnSOD was also reduced by denervation, whereas Beclin-1 was markedly elevated. This suggests that autophagic cell death could also play a significant part in denervation-induced muscle atrophy. Thus, despite prior chronic stimulation, denervation increases the apoptotic susceptibility of skeletal muscle by altering the Bax-to-Bcl-2 ratio, by increasing reactive oxygen species production, and by reducing the expression of MnSOD. Whether a more extensive stimulation paradigm would be more effective in attenuating apoptosis before muscle disuse remains to be determined.
O'Leary
Michael F N
MF
School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario M3J 1P3, Canada.
Hood
David A
DA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D004558:Electric Stimulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008931:Mitochondria, Muscle / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D009929:Organ Size / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV