Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue
Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue
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DOI：
10.1152/ajpcell.00065.2010
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发表时间：
2010-09-01
影响因子：
5.5
通讯作者：
Reid, Michael B.
中科院分区：
文献类型：
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作者：
Ferreira, Leonardo F.;Moylan, Jennifer S.;Reid, Michael B.
Ferreira LF，Moylan JS，Gilliam LA，Smith JD，Nikolova-Karakashian M，Reid MB.鞘磷脂酶刺激氧化剂信号传导以削弱骨骼肌并促进疲劳。美国生理学杂志细胞生理学299：C552-C560，2010年。首次发表于2010年6月2日; doi：10.1152/ajpcell.00065.2010。鞘磷脂酶（SMase）将膜鞘磷脂水解成神经酰胺，从而增加非肌肉细胞中的氧化剂。血清SMase活性在脓毒症和心力衰竭中升高，其中肌肉氧化剂增加，最大肌肉力量减少，疲劳加速。我们测试的假设，外源性SMase和积累的神经酰胺在肌肉中增加氧化剂在肌肉细胞中，抑制比力的非疲劳肌肉，并加速疲劳过程。我们还预计，抗氧化剂N-乙酰半胱氨酸（NAC）将阻止SMase对肌肉功能的影响。我们在体外研究了C2 C12肌管和小鼠膈肌对SMase处理的反应。我们观察到SMase引起肌管中总神经酰胺水平增加2.8倍。外源性神经酰胺和SMase使C2 C12肌管氧化活性提高15-35%（P < 0.05），膈肌纤维束氧化活性提高58-120%（P < 0.05）。SMase诱导的膈肌氧化活性增加被NAC阻止。外源性神经酰胺使膈肌最大肌力下降55%（P < 0.05），而SMase使膈肌最大肌力下降30%（P < 0.05），并加速了NAC治疗的疲劳效应。总之，我们的研究结果表明，SMase刺激神经酰胺氧化剂信号通路，导致肌肉无力和疲劳。
Ferreira LF, Moylan JS, Gilliam LA, Smith JD, Nikolova-Karakashian M, Reid MB. Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue. Am J Physiol Cell Physiol 299: C552-C560, 2010. First published June 2, 2010; doi: 10.1152/ajpcell.00065.2010.-Sphingomyelinase (SMase) hydrolyzes membrane sphingomyelin into ceramide, which increases oxidants in nonmuscle cells. Serum SMase activity is elevated in sepsis and heart failure, conditions where muscle oxidants are increased, maximal muscle force is diminished, and fatigue is accelerated. We tested the hypotheses that exogenous SMase and accumulation of ceramide in muscle increases oxidants in muscle cells, depresses specific force of unfatigued muscle, and accelerates the fatigue process. We also anticipated that the antioxidant N-acetylcysteine (NAC) would prevent SMase effects on muscle function. We studied the responses of C2C12 myotubes and mouse diaphragm to SMase treatment in vitro. We observed that SMase caused a 2.8-fold increase in total ceramide levels in myotubes. Exogenous ceramide and SMase elevated oxidant activity in C2C12 myotubes by 15-35% (P < 0.05) and in diaphragm muscle fiber bundles by 58-120% (P < 0.05). The SMase-induced increase in diaphragm oxidant activity was prevented by NAC. Exogenous ceramide depressed diaphragm force by 55% (P < 0.05), while SMase depressed maximal force by 30% (P < 0.05) and accelerated fatigue-effects opposed by treatment with NAC. In conclusion, our findings suggest that SMase stimulates a ceramide-oxidant signaling pathway that results in muscle weakness and fatigue.