Muscle stem cell activation in response to acute injury is promoted by transient exposure to neutrophil elastase

The molecular mechanisms underlying the activation of muscle stem cells in response to skeletal muscle injury are complex and only beginning to be elucidated since new tools were developed in the last decade. The immune response to tissue injury, often referred to as sterile inflammation, is a known key contributor to the mechanisms supporting muscle stem cell proliferation and differentiation in the muscle stem cell niche, but it is unclear whether muscle stem cell activation is also affected by the immune response. Here we show that neutrophil elastase, released in abundance during the first two days after muscle injury by infiltrating neutrophils, contributes to muscle stem cell re-entry into the cell cycle and commitment to the myogenic program. When neutrophil elastase is genetically ablated in mice, muscle stem cell activation is impaired, and muscle regeneration is delayed. Additionally, we identified cMet/mTOR and FGFR/ERK1/2 as two pathways activated by elastase in two different in vitro systems, via elastase-mediated cleavage and activation of pro-HGF and via elastase-mediated cleavage of extracellular matrix and release of bioactive FGF, respectively. While chronic exposure to neutrophil elastase impairs myoblast survival and differentiation, ultimately causing muscle regeneration defects, its transient presence in injured muscle during the first 24-48 hours post injury is beneficial and necessary. Thus, our results emphasize the importance of a tight regulation of the immune response for successful muscle regeneration, and provide strong evidence in support of a role for neutrophil elastase that is mainly to promote muscle healing in response to injury. Mechanistically, we highlight a key role for the cross-talk between neutrophils and muscle stem cells in muscle stem cell activation that involves neutrophil-derived elastase-mediated activation of mTOR and ERK1/2 via cMet and FGFR in muscle stem cells.