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Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells
James F. Markworth, … , Krishna Rao Maddipati, Susan V. Brooks
James F. Markworth, … , Krishna Rao Maddipati, Susan V. Brooks
Published August 4, 2020
Citation Information: JCI Insight. 2020;5(18):e137713. https://doi.org/10.1172/jci.insight.137713.
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Research Article Inflammation Muscle biology

Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells

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Abstract

Specialized proresolving mediators (SPMs) actively limit inflammation and expedite its resolution by modulating leukocyte recruitment and function. Here we profiled intramuscular lipid mediators via liquid chromatography-tandem mass spectrometry–based metabolipidomics following myofiber injury and investigated the potential role of SPMs in skeletal muscle inflammation and repair. Both proinflammatory eicosanoids and SPMs increased following myofiber damage induced by either intramuscular injection of barium chloride or synergist ablation–induced functional muscle overload. Daily systemic administration of the SPM resolvin D1 (RvD1) as an immunoresolvent limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokine expression, enhanced polymorphonuclear cell clearance, modulated the local muscle stem cell response, and polarized intramuscular macrophages to a more proregenerative subset. RvD1 had minimal direct impact on in vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs can modulate both infiltrating myeloid and resident muscle cell populations. These data reveal the efficacy of immunoresolvents as a novel alternative to classical antiinflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.

Authors

James F. Markworth, Lemuel A. Brown, Eunice Lim, Carolyn Floyd, Jacqueline Larouche, Jesus A. Castor-Macias, Kristoffer B. Sugg, Dylan C. Sarver, Peter C.D. Macpherson, Carol Davis, Carlos A. Aguilar, Krishna Rao Maddipati, Susan V. Brooks

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Figure 1

Dynamic shifts in muscle lipid mediators following skeletal muscle injury.

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Dynamic shifts in muscle lipid mediators following skeletal muscle injur...
(A) C57BL/6 mice received bilateral intramuscular injection of the tibialis anterior (TA) muscle with 50 μL of 1.2% barium chloride (BaCl2) to induce myofiber injury. Control mice received bilateral sham intramuscular injections with 50 μL of sterile saline. TA cross sections were stained for H&E, polymorphonuclear cells (PMNs, Ly6G), or monocytes/macrophages (CD68). Scale bars: 200 μm. (B) Heatmap of the top 25 muscle lipid mediators (based on partial least squares discriminant statistical analysis variable importance projection [PLS-DA VIP] score) modulated by muscle injury as determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). (C) Muscle mRNA expression of major lipid mediator biosynthetic enzymes and respective downstream lipid metabolites including cyclooxygenase-2 (COX-2, red), 5-lipoxygenase (5-LOX, orange), platelet-type 12-lipoxygenase (12-LOX, green), leukocyte-type 12/15-lipoxygenase (12/15-LOX, dark blue), and epoxygenase (CYP 450, purple) pathways. Downstream bioactive specialized proresolving lipid mediators (SPMs) detected in muscle are also shown (light blue). Bars show the mean ± SEM of 4–5 mice per group with dots representing data from each mouse. The sham injury time course was pooled for quantitative analysis. P values are by 1-way ANOVA followed by Holm-Šidák post hoc tests with sham-injured mice serving as controls. ND, below the limits of detection.

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