G9a Deficiency Increases Muscle Regeneration
Therapies that increase muscle tissue regeneration following injury, and possibly also normal maintenance and growth of muscle tissue, are of great interest at present. The widespread use of GLP-1 receptor agonists to induce calorie restriction causes loss of muscle mass as well as fat mass, and so there is a strong financial incentive for the research and development of means to force the body to build more muscle. There was already a strong financial incentive in the sense that everyone loses muscle with age, and frailty is a prevalent and harmful state of poor health, but for some reason that was never as motivating to the development community. Nonetheless, recent years have seen a number of interesting new discoveries in the regulation of muscle regeneration and growth. We will see whether any of them make it to the clinic in some form.
Muscle regenerative capacity declines with aging and disease, which leads to muscle loss and reduced lifespan. Muscle regenerative failure is related to a disrupted network orchestrated by multiple muscle-harbored cell types; whether and how the interplay between macrophages and myofibers contributes to this process is largely unknown. Herein, we report upregulation of histone methyltransferase G9a in both aged human muscle and mouse muscle after injury. Deletion of G9a in either myeloid cells or myofibers accelerates muscle regeneration.
Mechanistically, G9a down-regulates macrophage-derived interleukin 13 (IL13) and suppresses myofiber-derived myokine musclin, respectively, to inhibit myogenesis and macrophage phenotype transition during muscle regeneration. Either IL13 or musclin, per se, accelerated muscle regeneration, and their combined administration showed synergistic effects with therapeutic potentials for muscle degeneration disorders. Collectively, we highlight a crosstalk between macrophages and myofibers through IL13-Stat6 signaling and musclin, both regulated by G9a, which steers a pro-recovery microenvironment after muscle injury, with therapeutic potentials for muscle degeneration disorders.