Maresin 1 Repletion Improves Muscle Regeneration After Volumetric Muscle Loss

Abstract

The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and improved myogenesis, leading to enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.

Spatiotemporal mapping of immune and stem cell dysregulation after volumetric muscle loss

“…To understand the fibrotic response that develops after VML, we administered 2mm full-thickness punch biopsies to the tibialis anterior (TA) muscles of young adult mice. Consistent with previous results (9,17,18), we observed increased and persistent interstitial fibrosis as a result of VML injuries by staining with picrosirius red at 0-, 7-, 14-, and 28-days post injury (dpi) (Supplemental Figure 1). To decipher the mechanisms that confer the fibrotic behavior, we extracted cryosections of VML-injured murine tissues from 7-dpi, stained for hematoxylin and eosin (H&E) and annotated the tissue into zones of (1) complete muscle loss (defect zone), (2) remaining in-tact muscle (intact zone) and (3) a transition zone that partitions the lost muscle from the remaining musculature (Figure 1A-B).…”

“…The persistence of fibrotic gene expression and increase in myogenic terms aligns with tissue morphology at 14-dpi, where interstitial fibrosis is abundant while some myofibers have begun to repopulate around the defect (Figure 4B, Supplemental Figure 1). Together, these results indicate that the substantial resolution of inflammation by 14-dpi in the TA VML model facilitates some MuSC-mediated regeneration, but that the fibrotic program that yields long-term functional deficits (9,18) has already been established.…”

“…Uniquely, SAMs have been found to be activated by extended association with neutrophils ( 26 ), which is consistent with our previous findings ( 9 ) of persistent neutrophil infiltration. Given that SAMs and neutrophils are lipid-sensitive cells ( 9 , 18 , 47 ), additional exploration of the temporal recruitment and programming of Trem2 + Møs ( 49 ) by extracellular lipids after VML is warranted.…”

“…on myeloid and muscle stem cells [Internet]. JCI Insight 2020;5 (18). doi:10.1172/jci.insight.137713 51.…”