Sphingosine-1-Phosphate Enhances Satellite Cell Activation in Dystrophic Muscles through a S1PR2/STAT3 Signaling Pathway

Abstract

Sphingosine-1-phosphate (S1P) activates a widely expressed family of G protein-coupled receptors, serves as a muscle trophic factor and activates muscle stem cells called satellite cells (SCs) through unknown mechanisms. Here we show that muscle injury induces dynamic changes in S1P signaling and metabolism in vivo. These changes include early and profound induction of the gene encoding the S1P biosynthetic enzyme SphK1, followed by induction of the catabolic enzyme sphingosine phosphate lyase (SPL) 3 days later. These changes correlate with a transient increase in circulating S1P levels after muscle injury. We show a specific requirement for SphK1 to support efficient muscle regeneration and SC proliferation and differentiation. Mdx mice, which serve as a model for muscular dystrophy (MD), were found to be S1P-deficient and exhibited muscle SPL upregulation, suggesting that S1P catabolism is enhanced in dystrophic muscle. Pharmacological SPL inhibition increased muscle S1P levels, improved mdx muscle regeneration and enhanced SC proliferation via S1P receptor 2 (S1PR2)-dependent inhibition of Rac1, thereby activating Signal Transducer and Activator of Transcription 3 (STAT3), a central player in inflammatory signaling. STAT3 activation resulted in p21 and p27 downregulation in a S1PR2-dependent fashion in myoblasts. Our findings suggest that S1P promotes SC progression through the cell cycle by repression of cell cycle inhibitors via S1PR2/STAT3-dependent signaling and that SPL inhibition may provide a therapeutic strategy for MD.

Sphingosine-1-phosphate lyase expression in embryonic and adult murine tissues

“…Alternatively, and most likely, high SPL expression is required in tissues subjected to high S1P biosynthesis or uptake. Mice with reduced global SPL activity exhibit high levels of S1P in most tissues in comparison to control mice, as shown by others and ourselves ( 31,40,42,44,46 ). Even in tissues such as heart and skeletal muscle, wherein baseline SPL levels are very low to undetectable, SPL inhibition has signifi cant effects on S1P levels.…”

“…However, we have shown that SPL is induced in the murine heart and skeletal striated muscle in response to ischemia and chemical injury, respectively ( 44,46 ). SPL expression is regulated by transcriptional and post-transcriptional mechanisms during development and in response to radiation, ischemia and other insults.…”

“…LX2931, now in clinical trials for the treatment of rheumatoid arthritis, acts by inhibiting SPL and disrupting the S1P chemical gradient required for mature T-cell egress from the thymus and peripheral lymphoid organs and thereby preventing immune-mediated tissue damage ( 43 ). Studies have also implicated SPL as a potential target for cardioprotection, radioprotection, and recruitment of skeletal muscle stem cells for regeneration of injured muscle (44)(45)(46). SPL is down-regulated in colon cancer and other malignancies (47)(48)(49).…”

Hypothalamic S1P/S1PR1 axis controls energy homeostasis

“…1d, middle panel). After these results, we hypothesized that neuronal S1PR1 could be involved in the control of the energy homeostasis through the positive cross-talk mechanism, involving Jak/STAT3 cascade in neurons, as observed in other cell types [11][12][13][14]17 .…”

“…16). S1P/S1PRs axis plays a important role in the control of cardioprotection 11 , intestinal inflammation 12 , satellite cell activation 17 and tumour cells progression 13 through the persistent STAT3 activation. However, the role of hypothalamic S1P/S1PR1/STAT3 axis in the control of the energy homeostasis was not reported.…”