Aminov, E. | bioRxiv Science

bioRxiv2025

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/640469v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1d4fc1corg.highwire.dtl.DTLVardef@1f3a6b2org.highwire.dtl.DTLVardef@144f84corg.highwire.dtl.DTLVardef@109691b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Are circulating levels of the myokine irisin linked to type 2 diabetes? A systematic review and meta-analysis

BackgroundType II diabetes (T2DM) is one of the most prevalent metabolic disorders, and its multisystemic health consequences are widely known. Due to skeletal muscles ability to sequester a vast amount of glucose, muscle function and exercise have become a subject of much research into strategies to prevent and treat T2DM. Myokines are bioactive molecules released by muscle during contraction and involved in several biological processes such as metabolism, inflammation and behavior. Irisin, a recently discovered myokine, has been implicated in a vast array of physiological roles, including the ability to induce fat beiging. Since beige and brown fat both serve important roles in metabolic regulation, irisins role in the context of T2DM is the subject of ongoing investigations. MethodsWe systematically reviewed articles indexed in PubMed, Scopus and Web of Science that were published between 2011 and 2024, and compared circulating irisin levels in patients affected by T2DM and healthy subjects. As part of our systematic review of the literature, we performed meta-analysis of the data across all included articles, as well as stratified by body mass index (BMI), country of origin and by average irisin concentration in the control group. ResultsWe discovered great variability across the included studies in the average irisin levels detected, which spanned four orders of magnitude, hence the attempt at reducing variability by stratifying based on average levels in the control group. While the statistical power of our meta-analysis was decreased by the great variability in reported irisin concentrations, we nonetheless detected a consistent trend of decreased irisin concentration in T2DM patients compared with healthy controls, regardless of BMI, country of origin or average irisin concentration in the control group. ConclusionWith almost 60 articles included, ours is the first extensive systematic review and meta-analysis of irisin in T2DM, yet a highly statistically significant association between circulating irisin levels and T2DM could not be established due to the great variability of the data across include articles. Nonetheless we noticed a trend that is independent of BMI, suggesting a direct relationship between T2DM and irisin that is likely not secondary to diabetic sarcopenia. While our work encourages further research into irisins potential role in T2DM pathogenesis, the reproducibility of irisin detection methods in biological samples should be determined and standardized protocols should be made available to the research and clinical communities.

physiology↗