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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 6

Resolvin D1 improves recovery of isometric muscle strength.

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Resolvin D1 improves recovery of isometric muscle strength.
(A) C57BL/6 ...
(A) C57BL/6 mice received bilateral intramuscular injection of the TA muscle with 50 μL of 1.2% BaCl2 to induce myofiber injury. Mice were treated with RvD1 (100 ng) or vehicle (0.1% ethanol) for 14 days. TA muscle function was tested for maximal isometric nerve-stimulated in situ contractile force (Po) with age- and sex-matched mice serving as uninjured controls. Absolute maximal isometric force (mN) generated by the TA muscle was measured and used to calculate maximal specific isometric contractile force (sPo, mN/mm2). Representative force traces obtained from uninjured and injured TA muscles are shown. (B) TA cross sections were stained with conjugated phalloidin to label the total muscle fiber population or for muscle fiber type with antibodies against MHC I, IIa, and IIb. Type IIx fibers remain unstained (black) and are identified by lack of fluorescence staining. Cell nuclei and the basal lamina were counterstained with DAPI and laminin antibody, respectively. Scale bars: 200 μm. (C) Quantitative analysis of percent muscle fiber type composition and mean fiber CSA split by muscle fiber type as determined by MuscleJ. (D) Quantification of overall TA muscle CSA, the percentage of centrally nucleated (regenerating) myofibers, mean regenerating myofiber CSA, and percent frequency distribution of regenerating fiber CSA as determined by MuscleJ. (E) TA cross sections were stained for H&E, total macrophages (CD68+ cells), and M2-like macrophages (CD163+ cells). Scale bars: 200 μm. (F) Quantification of the histological presence of total muscle macrophages and M2-like macrophages. Cell counts were performed manually throughout the entire muscle cross section and then normalized to tissue surface area as determined by MuscleJ. Bars show the mean ± SEM of 5–10 mice per group with dots representing data from each mouse. P values were determined by 1-way ANOVA followed by pairwise Holm-Šidák post hoc tests (A and F) or 2-tailed unpaired t tests (C and D).

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