Abstract
Muscles of older animals are more susceptible to injury and regenerate poorly, in part due to a persistent inflammatory response. The janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway mediates inflammatory signaling and is tightly regulated by the suppressor of cytokine signaling (SOCS) proteins, especially SOCS3. SOCS3 expression is altered in the muscle of aged animals and may contribute to the persistent inflammation and impaired regeneration. To test this hypothesis, we performed myotoxic injuries on mice with a tamoxifen-inducible deletion of SOCS3 specifically within the muscle stem cell compartment. Muscle stem cell-specific SOCS3 deletion reduced muscle mass at 14 days post-injury (-14%, P < 0.01), altered the myogenic transcriptional program, and reduced myogenic fusion based on the number of centrally-located nuclei per muscle fiber. Despite the delay in myogenesis, muscles with a muscle stem cell-specific deletion of SOCS3 were still able to regenerate after a single bout or multiple bouts of myotoxic injury. A reduction in SOCS3 expression in muscle stem cells is unlikely to be responsible for the incomplete muscle repair in aged animals.
Highlights
Successful skeletal muscle repair is essential for the maintenance of muscle integrity to maintain quality of life
We previously reported that specific deletion of SOCS3 in mature skeletal muscle fibers enhances the inflammatory response after myotoxic injury but does not impair regeneration [9]
Skeletal muscle is a heterogenous tissue comprised of multiple cell types that express SOCS3 including mature muscle fibers, immune/inflammatory cells, fibroblasts, and the muscle stem cells, making it difficult to isolate a pure population of SOCS3-deficient cells
Summary
Successful skeletal muscle repair is essential for the maintenance of muscle integrity to maintain quality of life. When injured, damaged muscle fibers release factors that promote recruitment of inflammatory cells and the activation and proliferation of muscle stem cells. Activated muscle stem cells proliferate, migrate, and fuse to repair damaged muscle fibers in a process highly dependent on a properly regulated inflammatory response [1]. The family member Tinman was discovered to be a major regulator of cell fate and muscle development via the Janus kinase (Jak)/Signal transducers and activators of transcription (Stat) Jak/Stat signaling pathway [2]. Jak/Stat signaling has been shown to regulate muscle stem cell activity, as mice with a muscle stem cell specific deletion of STAT3 demonstrate impaired myogenesis resulting from altered myogenic fusion [3]. One key family of negative regulators of Jak/Stat signaling are the suppressor of cytokine signalling (SOCS) proteins.
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