Melatonin prevents oxidative stress-mediated mitochondrial permeability transition and death in skeletal muscle cells.
Oxidative stress-induced mitochondrial dysfunction plays a crucial role in the pathogenesis of a wide range of diseases including muscle disorders. In this study, we demonstrate that melatonin readily rescued mitochondria from oxidative stress-induced dysfunction and effectively prevented subsequent apoptosis of primary muscle cultures prepared from C57BL/6J mice. In particular, melatonin (10(-4)-10(-6) m) fully prevented myotube death induced by tert-butylhydroperoxide (t-BHP; 10 microm-24 hr) as assessed by acid phosphatase, caspase-3 activities and cellular morphological changes. Using fluorescence imaging, we showed that the mitochondrial protection provided by melatonin was associated with an inhibition of t-BHP-induced reactive oxygen species generation. In line with this observation, melatonin prevented t-BHP-induced mitochondrial depolarization and mitochondrial permeability transition pore (PTP) opening. This was associated with a highly reduced environment as reflected by an increased glutathione content and an increased ability to maintain mitochondrial pyridine nucleotides and glutathione in a reduced state. Using isolated mitochondria, in a similar manner as cyclosporin A, melatonin (10(-8)-10(-6) m) desensitized the PTP to Ca(2+) and prevented t-BHP-induced mitochondrial swelling, pyridine nucleotide and glutathione oxidation. In conclusion, our findings suggest that inhibition of the PTP essentially contributes to the protective effect of melatonin against oxidative stress in myotubes.
Hibaoui
Youssef
Y
Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, Quai Ernest-Ansermet, Geneva, Switzerland.
Roulet
Emmanuelle
E
Ruegg
Urs T
UT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D002492:Central Nervous System Depressants; D017382:Reactive Oxygen Species; D020122:tert-Butylhydroperoxide; D008550:Melatonin