STAT3 signaling controls satellite cell expansion and skeletal muscle repair

Abstract

The progression of disease- and age-dependent skeletal muscle wasting results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair1–10. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions11–13. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting14,15, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues16–19. Here we show that IL-6–activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases.

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation

“…The discovery of murine MuSCs capable of robustly regenerating and restoring strength to injured muscles (1,3,7,(16)(17)(18)(19), and a means for their expansion in culture using inducers such as p38 MAPK inhibitors, has provided a framework for their future clinical application (22,(51)(52)(53). Moreover, recent strides in the isolation and characterization of their human counterparts from tissues or as derivatives from human embryonic stem (ES) or induced pluripotent stem (iPS) cells (54-59) now facilitate the use of these potent cell types as a muscle cell therapeutic.…”

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

“…It has also been reported that inhibition of the IL-6 intracellular mediator, namely the Jak/Stat pathway, stimulates muscle regeneration in both aged and dystrophic mice [60,61].…”

Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles

“…Alterations of these networks have been associated to muscular chronic diseases and aging. [10][11][12][13] Different biological processes evolved to preserve tissue homeostasis in eukaryotes. Among them, autophagy is emerging as a key protective mechanism in many tissues.…”