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.
Highlights
Duchenne muscular dystrophy (DMD) is the most common form of MD, a disease characterized by progressive loss of skeletal muscle strength associated with pathological features including muscle pseudohypertrophy, necrosis and regeneration, variation in fiber size, and eventual muscle replacement by adipose tissue [1]
The expression levels of genes encoding S1PR3-5 increased over time but remained low compared to those encoding S1PR1 and S1P receptor 2 (S1PR2) (Figures 1E and F)
JTE-013 treatment was associated with a significant decrease in the number of satellite cells (SCs) when evaluated by FACS analysis (Figure 6H). These findings demonstrate that S1PR2 activation and downstream activation of Signal Transducer and Activator of Transcription 3 (STAT3) are essential for efficient muscle regeneration and SC proliferation
Summary
Duchenne muscular dystrophy (DMD) is the most common form of MD, a disease characterized by progressive loss of skeletal muscle strength associated with pathological features including muscle pseudohypertrophy, necrosis and regeneration, variation in fiber size, and eventual muscle replacement by adipose tissue [1]. Disruption of the normal bridge between ECM, DGC and cytoskeleton in patients with DMD reduces membrane stability, resulting in myofiber injury and necrosis [3]. Disruption of the muscle architecture by traumatic injury or genetic instability results in exposure of SCs to bioactive factors released from injured muscle fiber and its niche, leading to their activation [5]. The chronic/degenerative phase of DMD is caused by a failure of regeneration to keep up with ongoing injury and destruction of muscle fibers. This may be accounted for in part by an exhaustion of SC reserves or their myogenic potential. Development of methods that replenish the endogenous SC compartment, allow ex vivo expansion of donor SCs for cellular therapy, or enhance the myogenic potential of endogenous or donor SCs are each being explored as therapeutic strategies in DMD [7]
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