Metabolipidomic profiling reveals an age‐related deficiency of skeletal muscle pro‐resolving mediators that contributes to maladaptive tissue remodeling

Abstract

Specialized pro‐resolving mediators actively limit inflammation and support tissue regeneration, but their role in age‐related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography‐tandem mass spectrometry and tested whether treatment with the pro‐resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro‐resolving mediators 8‐oxo‐RvD1, resolvin E3, and maresin 1, as well as many anti‐inflammatory cytochrome P450‐derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro‐inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E2) and 12‐lipoxygenase (e.g., 12‐hydroxy‐eicosatetraenoic acid), but aged mice produced fewer markers of pro‐resolving mediators including the lipoxins (15‐hydroxy‐eicosatetraenoic acid), D‐resolvins/protectins (17‐hydroxy‐docosahexaenoic acid), E‐resolvins (18‐hydroxy‐eicosapentaenoic acid), and maresins (14‐hydroxy‐docosahexaenoic acid). Similar absences of downstream pro‐resolving mediators including lipoxin A4, resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro‐resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non‐steroidal anti‐inflammatory drugs.

Maresin 1 Repletion Improves Muscle Regeneration After Volumetric Muscle Loss

“…Consistent with previous observations in an analogous model in the rectus femoris (10,25), defects below the critical threshold regenerate, while larger defects result in long-term increases in fibrosis and reductions in contractile force. Using this model of regenerative and degenerative VML, we performed metabolipidomics analysis (40) over a time course to understand signaling factors that contribute to the observed changes in fibrosis. We detected a stark imbalance of pro-inflammatory eicosanoids to pro-resolving lipid mediators in degenerative VML injuries, which correlates with our previous observations of sustained inflammation and persistent neutrophil (10) and macrophage (6) presence following degenerative VML.…”

The Resolvin D2-GPR18 Axis Enhances Bone Marrow Function and Limits Hepatic Fibrosis in Aging

“…However, Resolvin D1 (RvD1), which is another member of the D-series resolvin family, was shown to limit neutrophil infiltration into the peritoneum (2) and reduced neutrophils in the lungs after remote organ ischemia reperfusion injury (4) in old animals. Another study demonstrated that RvD1 treatment to aged mice reduced skeletal muscle inflammation and fibrosis, again suggesting a role for D-Series resolvins in limiting inflammation and tissue injury in aging (28). The mechanisms of actions of RvD1 in aging are not fully known.…”

Low serum Maresin-1 levels are associated with non-alcoholic fatty liver disease: a cross-sectional study

“…Recently, Félix-Soriano et al found that MaR1 was significantly reduced in adipose tissue in aged HFD-induced obese mice compared to young normal controls [ 33 ]. Markworth et al also showed that aged mouse muscle displayed significantly lower MaR1 levels than the young mouse muscle [ 34 ]. These data suggested that ageing is associated with MaR1 deficiency.…”