title: Sphingosine 1-phosphate protects mouse extensor digitorum longus skeletal muscle during fatigue.
abstract: 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 Ca(2+)-free solutions, in agreement with the hypothesis that SPH action is dependent on its conversion to S1P by the Ca(2+)-requiring enzyme SK. In contrast to SPH, S1P produced its positive effects on fatigue in Ca(2+)-free conditions, indicating that S1P action does not require Ca(2+) 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.
authors.affiliation: Department of Human Anatomy and Physiology, University of Padua, Via Marzolo 3, 35131 Padua, Italy. daniela.danieli@unipd.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Danieli-Betto
authors.forename: Elena
authors.initials: E
authors.lastname: Germinario
authors.forename: Alessandra
authors.initials: A
authors.lastname: Esposito
authors.forename: Aram
authors.initials: A
authors.lastname: Megighian
authors.forename: Menotti
authors.initials: M
authors.lastname: Midrio
authors.forename: Barbara
authors.initials: B
authors.lastname: Ravara
authors.forename: Ernesto
authors.initials: E
authors.lastname: Damiani
authors.forename: Luciano Dalla
authors.initials: LD
authors.lastname: Libera
authors.forename: Roger A
authors.initials: RA
authors.lastname: Sabbadini
authors.forename: Romeo
authors.initials: R
authors.lastname: Betto
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology*; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018763:Muscle Fatigue / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D000099157:Sphingosine Kinase
chemical_list: D002118:Calcium; D007211:Indoles; D008246:Lysophospholipids; D008301:Maleimides; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C088060:bisindolylmaleimide