Sphyngomyelin derivatives influence the trophism of skeletal muscles.

Large evidence demonstrates that sphingomyelin derivatives exert important extracellular actions. Among these lipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), present at high levels in plasma, exert their action by stimulating specific receptors expressed in almost all tissues. As a result, S1P and SPC are able to control important cell functions, such as growth, migration, proliferation and survival. Recent evidence, produced in our laboratory, suggests that these two lipids are trophic factors of skeletal muscle. Skeletal muscle fibres express at least three of the five specific S1P/SPC receptors. One of these receptors, S1P1, is localized at cell membrane and its expression level and localization vary depending on diverse conditions, such as fibre type, animal age, loss of innervations, and during regeneration. Importantly, we have recently demonstrated that S1P sustains contractile activity of skeletal muscle, particularly during fatigue. Finally, we have also evidenced the presence of a rheostat mechanism at muscle fibre surface competent to convert a potentially adverse lipid, sphingosine (SPH), into a positive compound, S1P, an action operated by the enzyme SPH kinase. Based on these results, we advanced the hypothesis that S1P and SPC could be trophic factors of skeletal muscle and their action regulated by contractile activity. As a consequence, the regulatory action of sphingomyelin derivatives is probably compromised under disuse conditions, particularly in the microgravity environment. To establish the trophic function of S1P and SPC (but also of SPH, being the precursor of S1P), we have utilized a typical experimental model of disuse, muscle denervation, by employing two opposite approaches: the denervated muscle was either treated with extra doses of the lipids or the level of circulating S1P was reduced. The results show that the increased level of both SPH, SPC and S1P, delivered at constant rate to the muscle through mini-osmotic pumps, determined a significant reduction of the expected atrophy produced by the absence of the nerve. Among the three lipids, SPC was the most successful by producing early and substantial trophic effects, while SPH was efficacious in slowing the typical slow-to-fast transformation of denervated muscle. The lipids also affected the expression of myogenic factors, suggesting they could regulate the processing of satellite cells. On the other hand, the marked reduction of circulating S1P, obtained by treating the denervated animal with an antibody specific for the lipid, caused a dramatic increase of the atrophy of the denervated muscle. These results thus identify sphingomyelin derivatives as trophic factors of skeletal muscle and, as a consequence, suggest that the regulation of their plasma level could represent a suitable intervention to attenuate, if not prevent, the progressive muscle atrophy generated by space flight as well as in diverse muscle disuse condition