Immunoresolvents Support Skeletal Myofiber Regeneration via Actions on Myeloid and Muscle Stem Cells

Abstract

150-word limit):Specialized pro-resolving mediators (SPMs) actively limit inflammation and expedite its resolution. Here we profiled intramuscular lipid mediators following injury and investigated the role of SPMs in skeletal muscle inflammation and repair. Both eicosanoids and SPMs increased following myofiber damage induced by intramuscular injection of barium chloride or functional overload. Daily systemic administration of resolvin D1 (RvD1) limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokines, enhanced polymorphonuclear cell clearance, modulated muscle stem cells, and polarized macrophages to a more pro-regenerative subset. RvD1 had minimal direct impact on in-vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs influence modulate both infiltrating myeloid and resident muscle cells. These data reveal the efficacy of immunoresolvents as a novel alternative to classical anti-inflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.3 Introduction:

Lipidomic Profiling Reveals an Age-Related Deficiency of Skeletal Muscle Proresolving Mediators that Contributes to Maladaptive Tissue Remodeling

“…Treatment of aged mice with the prototypical SPM, RvD1, at the time of injury suppressed muscle expression of both pro-and anti-inflammatory cytokines including MCP-1, IL-1β, and IL-10. Despite this, unlike our prior study in young mice (Markworth et al, 2020), in the present study we were unable to demonstrate in aged mice a reduction in MΦ infiltration of muscle in response to RvD1 treatment. Moreover, other inflammationrelated genes (e.g.…”

“…The ability of systemic RvD1 administration to limit PMN recruitment is well-described for certain experimental models of acute inflammation (Norling, Dalli, Flower, Serhan, & Perretti, 2012). In contrast, we have been unable to demonstrate this in the context of sterile skeletal muscle injury in either young (Markworth et al, 2020), or old mice (present study). Prior studies in cardiac muscle found that systemic injection of RvD1 was also unable to limit PMN appearance following myocardial infarction (Halade, Kain, & Serhan, 2018;Kain et al, 2015).…”

“…Moreover, other inflammationrelated genes (e.g. TNFα and IL-6) that were markedly suppressed in young mice treated with RvD1 (Markworth et al, 2020), showed only statistical trends towards suppression in aged muscle here. These data suggest that RvD1 was unable to fully overcome heightened muscle myeloid cell infiltration in aged mice.…”

“…Each SPM family is enzymatically derived from essential dietary polyunsaturated fatty acid (PUFA) substrates via the coordinated actions of the 5-12-, and 15-lipoxygenase (LOX) pathways and share defining actions to inhibit further PMN recruitment to the site of inflammation, while stimulating MΦ functions necessary for timely resolution (Serhan & Levy, 2018). SPMs are produced in response to muscle injury in both rodents (Giannakis et al, 2019;Markworth et al, 2020) and humans (Gangemi et al, 2003;Markworth et al, 2013;Vella et al, 2019), suggesting that they may play an important role in the immunological and adaptive responses to myofiber damage (Markworth, Maddipati, & Cameron-Smith, 2016).…”

“…Non-steroidal anti-inflammatory drugs (NSAIDs) lessen the harmful effects of muscle injury in the short term by reducing strength loss and muscle soreness (Morelli, Brown, & Warren, 2017); however, NSAIDs also delay timely resolution of the acute inflammatory response and can impair myofiber growth and regeneration (Markworth et al, 2016). In contrast to NSAIDs, therapeutic administration of resolution agonists such as native SPMs or drug mimetics, termed immunoresolvents, can actually improve muscle regenerative outcomes in young mice and may thus offer an attractive alternative to classical anti-inflammatory approaches to the clinical management of muscle injuries (Giannakis et al, 2019;Markworth et al, 2020).…”