Sphingosine 1-phosphate signaling is involved in skeletal muscle regeneration

Abstract

) is a bioactive lipid known to control cell growth that was recently shown to act as a trophic factor for skeletal muscle, reducing the progress of denervation atrophy. The aim of this work was to investigate whether S1P is involved in skeletal muscle fiber recovery (regeneration) after myotoxic injury induced by bupivacaine. The postnatal ability of skeletal muscle to grow and regenerate is dependent on resident stem cells called satellite cells. Immunofluorescence analysis demonstrated that S1P-specific receptors S1P1 and S1P3 are expressed by quiescent satellite cells. Soleus muscles undergoing regeneration following injury induced by intramuscular injection of bupivacaine exhibited enhanced expression of S1P1 receptor, while S1P3 expression progressively decreased to adult levels. S1P 2 receptor was absent in quiescent cells but was transiently expressed in the early regenerating phases only. Administration of S1P (50 M) at the moment of myotoxic injury caused a significant increase of the mean crosssectional area of regenerating fibers in both rat and mouse. In separate experiments designed to test the trophic effects of S1P, neutralization of endogenous circulating S1P by intraperitoneal administration of anti-S1P antibody attenuated fiber growth. Use of selective modulators of S1P receptors indicated that S1P1 receptor negatively and S1P3 receptor positively modulate the early phases of regeneration, whereas S1P2 receptor appears to be less important. The present results show that S1P signaling participates in the regenerative processes of skeletal muscle. sphingosine 1-phosphate receptors; satellite cells SPHINGOSINE 1-PHOSPHATE (S1P) is a bioactive lysolipid known to regulate many critical biological processes, such as cell proliferation, survival, migration, and angiogenesis (15, 42). The extracellular action of S1P is exerted by binding to five specific cell surface G protein-coupled S1P receptors, S1P 1 -S1P 5 (4). S1P 1 , S1P 2 , and S1P 3 are expressed in all mammalian tissues, whereas S1P 4 and S1P 5 are more tissue specific. Genetic deletion of S1P 1 receptor is fatal to embryos (19), and the simultaneous deletion of both S1P 2 and S1P 3 receptors produces perinatal lethality, while S1P 2 -deficient mice are apparently healthy (16). The distinctive combination of individual S1P receptors, differentially coupled to heterotrimeric G proteins, determines in a given cell the specific biological response produced by S1P (42). S1P receptor-dependent signaling has been demonstrated in skeletal muscle cells. The mRNAs of S1P 1 -S1P 3 receptors are detectable in the myogenic C2C12 cell line derived from mouse satellite cells, with S1P 1 expression being the highest (25, 36). The relative expression of S1P receptors changes during myogenic differentiation of C2C12 cells, particularly that of S1P 2 , which progressively diminishes during differentiation and becomes almost absent by the time myotubes are formed (22). Consistently in rat adult skeletal muscle RT-PCR and Western blot data demonstrated the exp...

Satellite Cells and the Muscle Stem Cell Niche

“…This action of S1P on satellite cell activation and muscle regeneration is in line with the proliferative, proinflammatory (through COX-2) and antiapoptotic (through inhibition of caspase-3 and BAX) functions of S1P-mediated pathways in general. Accumulating evidence indicates that S1P, being one of the more soluble sphingolipids, acts through S1P receptors (S1PRs; a group of highaffinity G protein-coupled receptors) on satellite cells in an autocrine/paracrine fashion (76,122). In addition, abnormal modulation of S1P activity is also involved in the pathology of muscular dystrophy (as exemplified in mdx mice) (317).…”

STAT3 in Skeletal Muscle Function and Disorders

“…The expression of several transcription factors, including STAT3, was shown to be upregulated in diaphragm muscles from 6 week old mdx mice compared to WT mice [57]. Sphingosine-1 phosphate (S1P) is a bioactive lipid that modulates the activity of many different pathways (e.g., AKT signaling and Ras/MAP kinase cascade), and has been implicated in the activation of satellite cells [24,94,95]. In a study evaluating the role of S1P in muscle satellite cell function, results demonstrated that S1P catabolism was associated with lower STAT3 activation and poor satellite cell function [96].…”

Sphingolipid Metabolism, Oxidant Signaling, and Contractile Function of Skeletal Muscle

“…Two sphingosine-1-phosphate receptors, S1P 1 and S1P 3 , are expressed by quiescent satellite cells and are localized to the sarcolemma and T-tubules of skeletal muscle fibers; S1P 1 is found at the neuromuscular junction (125). Regeneration of soleus muscle after injury stimulates the expression of these receptors, whereas administration of sphingosine-1-phosphate at the time of injury increases the cross-sectional area of regenerating fibers; conversely, administration of anti-sphingosine-1-phosphate antibody has the opposite effect, attenuating fiber growth (27). Sarcolemmal receptors are likely to mediate these trophic effects, suggesting that sphingosine-1-phosphate can function as a growth factor for muscle fibers.…”

“…5). Danieli-Betto et al (27) demonstrated the capacity of sphingosine-1-phosphate to oppose fatigue. In vitro exposure of murine EDL to sphingosine-1-phosphate slowed the decline in force during fatiguing contractions; final force was 40% greater than control.…”