title: Effects of S1P on skeletal muscle repair/regeneration during eccentric contraction.
abstract: Skeletal muscle regeneration is severely compromised in the case of extended damage. The current challenge is to find factors capable of limiting muscle degeneration and/or potentiating the inherent regenerative program mediated by a specific type of myoblastic cells, the satellite cells. Recent studies from our groups and others have shown that the bioactive lipid, sphingosine 1-phosphate (S1P), promotes myoblast differentiation and exerts a trophic action on denervated skeletal muscle fibres. In the present study, we examined the effects of S1P on eccentric contraction (EC)-injured extensor digitorum longus muscle fibres and resident satellite cells. After EC, skeletal muscle showed evidence of structural and biochemical damage along with significant electrophysiological changes, i.e. reduced plasma membrane resistance and resting membrane potential and altered Na(+)  and Ca(2+)  current amplitude and kinetics. Treatment with exogenous S1P attenuated the EC-induced tissue damage, protecting skeletal muscle fibre from apoptosis, preserving satellite cell viability and affecting extracellular matrix remodelling, through the up-regulation of matrix metalloproteinase 9 (MMP-9) expression. S1P also promoted satellite cell renewal and differentiation in the damaged muscle. Notably, EC was associated with the activation of sphingosine kinase 1 (SphK1) and with increased endogenous S1P synthesis, further stressing the relevance of S1P in skeletal muscle protection and repair/regeneration. In line with this, the treatment with a selective SphK1 inhibitor during EC, caused an exacerbation of the muscle damage and attenuated MMP-9 expression. Together, these findings are in favour for a role of S1P in skeletal muscle healing and offer new clues for the identification of novel therapeutic approaches to counteract skeletal muscle damage and disease.
authors.affiliation: Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sassoli
authors.forename: Lucia
authors.initials: L
authors.lastname: Formigli
authors.forename: Francesca
authors.initials: F
authors.lastname: Bini
authors.forename: Alessia
authors.initials: A
authors.lastname: Tani
authors.forename: Roberta
authors.initials: R
authors.lastname: Squecco
authors.forename: Chiara
authors.initials: C
authors.lastname: Battistini
authors.forename: Sandra
authors.initials: S
authors.lastname: Zecchi-Orlandini
authors.forename: Fabio
authors.initials: F
authors.lastname: Francini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Meacci
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000032:analysis; D053148:Caspase 3; D053179:Caspase 7; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D012964:Sodium / Q000032:analysis; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014945:Wound Healing; D000099157:Sphingosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002118:Calcium; D053148:Caspase 3; D053179:Caspase 7; D008246:Lysophospholipids; D020780:Matrix Metalloproteinase 9; D017853:Phosphotransferases (Alcohol Group Acceptor); D012964:Sodium; D013110:Sphingosine; D000099157:Sphingosine Kinase; C466999:SPHKAP protein, human; C060506:sphingosine 1-phosphate