Abstract
MicroRNAs (miRNAs) have recently been implicated in muscle stem cell function. miR-127 is known to be predominantly expressed in skeletal muscle, but its roles in myogenic differentiation and muscle regeneration are unknown. Here, we show that miR-127 is upregulated during C2C12 and satellite cell (SC) differentiation and, by establishing C2C12 cells stably expressing miR-127, demonstrate that overexpression of miR-127 in C2C12 cells enhances myogenic cell differentiation. To investigate the function of miR-127 during muscle development and regeneration in vivo, we generated miR-127 transgenic mice. These mice exhibited remarkably accelerated muscle regeneration compared with wild-type mice by promoting SC differentiation. Mechanistically, we demonstrated that the gene encoding sphingosine-1-phosphate receptor 3 (S1PR3), a G-protein-coupled receptor for sphingosine-1-phosphate, is a target of miR-127 required for its function in promoting myogenic cell differentiation. Importantly, overexpression of miR-127 in muscular dystrophy model mdx mice considerably ameliorated the disease phenotype. Thus, our findings suggest that miR-127 may serve as a potential therapeutic target for the treatment of skeletal muscle disease in humans.
Highlights
Skeletal muscle regeneration relies on a small population of stem cells, termed satellite cells (SCs), that reside beneath the basal lamina of myofibers.[1,2] SCs are normally quiescent; in response to stress or injury, they become activated and proliferate, differentiate, and fuse into multinucleated myotubes.[3,4] Abnormalities in SC activation, proliferation, or differentiation result in skeletal muscle dysfunction during regeneration, leading to the development of muscle disease.[5]
These results indicate that miR-127 significantly potentiates myogenic cell differentiation in vitro
Recent studies have revealed the functional significance of miRNAs in regulating SC activation, proliferation, Figure 6 miR-127 enhances myogenic differentiation by targeting S1PR3. (a) Quantitative real-time polymerase chain reaction analysis of S1PR3 fold overexpression in miR-127 OE cells transiently transfected with an S1PR3 expression plasmid; cells transfected with empty vector served as a negative control (NC)
Summary
Skeletal muscle regeneration relies on a small population of stem cells, termed satellite cells (SCs), that reside beneath the basal lamina of myofibers.[1,2] SCs are normally quiescent; in response to stress or injury, they become activated and proliferate, differentiate, and fuse into multinucleated myotubes.[3,4] Abnormalities in SC activation, proliferation, or differentiation result in skeletal muscle dysfunction during regeneration, leading to the development of muscle disease.[5]. MiR-127, located within an miRNA cluster in the Dlk1-Dio[3] region of both mouse and human genomes,[20,21] has been implicated in the development of breast cancer, hepatocellular cancer, glioblastoma, and lung carcinomas.[22,23,24,25] Interestingly, several miRNAs in this cluster, including miR-431, miR-127, miR-432, miR-433, miR-434, and miR-136, have been reported to be predominantly expressed in skeletal muscle and brain tissues.[16,26,27] Our group and others recently demonstrated that miR-431 has an important role in muscle stem cell function and muscle regeneration,[16,28] and it is conceivable that miR-127 might be involved in muscle development or SC functions during postnatal myogenesis and regeneration
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