Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Leonardo F. Ferreira, Jennifer S. Moylan, Laura A.A. Gilliam, Jeffrey D. Smith, Mariana Nikolova-Karakashian, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)C552-C560
JournalAmerican Journal of Physiology - Cell Physiology
Volume299
Issue number3
DOIs
StatePublished - Sep 2010

Keywords

  • Ceramide
  • Diaphragm
  • Exercise
  • Inflammation
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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