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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Sphingosine 1-phosphate protects mouse extensor digitorum longus skeletal muscle during fatigue

¹Department of Human Anatomy and Physiology and ²Department of Biomedical and Experimental Sciences, University of Padua, Padua; ³Muscle Biology and Physiopathology Unit, Consiglio Nazionale delle Ricerche Institute of Neuroscience, Padua, Italy; and ⁴Department of Biology and Heart Institute, San Diego State University, San Diego, California

Submitted 17 May 2004 ; accepted in final form 18 January 2005

Sphingomyelin derivatives exert various second messenger actions in numerous tissues. Sphingosine (SPH) and sphingosine 1-phosphate (S1P) are two major sphingomyelin derivatives present at high levels in blood. The aim of the present work was to investigate whether S1P and SPH exert relevant actions in mouse skeletal muscle contractility and fatigue. Exogenous S1P and SPH administration caused a significant reduction of tension decline during fatigue of extensor digitorum longus muscle. Final tension after the fatiguing protocol was 40% higher than in untreated muscle. Interestingly, N,N-dimethylsphingosine, an inhibitor of SPH kinase (SK), abolished the effect of supplemented SPH but not that of S1P, suggesting that SPH acts through its conversion to S1P. Moreover, SPH was not effective in Ca²⁺-free solutions, in agreement with the hypothesis that SPH action is dependent on its conversion to S1P by the Ca²⁺-requiring enzyme SK. In contrast to SPH, S1P produced its positive effects on fatigue in Ca²⁺-free conditions, indicating that S1P action does not require Ca²⁺ entry and most likely is receptor mediated. The effects of S1P could be ascribed in part to its ability to prevent the reduction (–20 mV) of action potential amplitude caused by fatigue. In conclusion, these results indicate that extracellular S1P has protective effects during the development of muscle fatigue and that the extracellular conversion of SPH to S1P may represent a rheostat mechanism to protect skeletal muscle from possible cytotoxic actions of SPH.

sphingosine kinase; action potential; sphingosine

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