Date Published: February 27, 2019
Publisher: Public Library of Science
Author(s): Kristy Swiderski, Marissa K. Caldow, Timur Naim, Jennifer Trieu, Annabel Chee, René Koopman, Gordon S. Lynch, Stephen E. Alway.
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.
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 . In drosophila, 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 . Since then, 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 .
It is widely accepted that SOCS3 is expressed by multiple cell types in regenerating skeletal muscles, but its relative contribution to altered muscle inflammation and regeneration has yet to be established. We previously reported that specific deletion of SOCS3 in mature muscle fibers enhanced the inflammatory response after myotoxic injury but did not impair regeneration . Using mice specifically lacking SOCS3 in Pax7-expressing muscle stem cells we have now shown in vivo that SOCS3 deletion alters the myogenic program but does not impact overall muscle regeneration post-injury.