Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
Aging Cell. 2021 Jun;20(6):e13393. doi: 10.1111/acel.13393. Epub 2021 Jun 2.
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 E ) 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 A , 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.
专门的促解决介质积极限制炎症并支持组织再生，但它们在与年龄相关的肌肉功能障碍中的作用尚未得到探索。我们通过液相色谱-串联质谱法对衰老肌肉中的介质脂质组进行了分析，并测试了促解决介质 resolvin D1 (RvD1) 的治疗是否可以使衰老肌肉的再生能力恢复活力。衰老的小鼠表现出慢性肌肉炎症，这与促解决介质 8-oxo-RvD1、resolvin E3 和maresin 1 的基础缺乏以及许多抗炎细胞色素 P450 衍生的脂质环氧化物有关。在肌肉损伤后，年轻和衰老的小鼠产生了相似数量的大多数促炎环氧化酶（例如前列腺素 E）和 12-脂氧合酶（例如 12-羟基二十碳四烯酸）代谢物，但衰老的小鼠产生的促解决介质标志物较少，包括脂氧素（15-羟基二十碳四烯酸）、D-解决素/保护素（17-羟基二十二碳六烯酸）、E-解决素（18-羟基二十碳五烯酸）和maresin（14-羟基二十二碳六烯酸）。衰老肌肉中类似的下游促解决介质（包括脂氧素 A、resolvin D6、保护素 D1/DX 和maresin 1）的缺失与更大的炎症、肌纤维再生受损和力量恢复延迟有关。每天腹膜内注射 RvD1 对肌肉内白细胞浸润和肌纤维再生的影响很小，但可抑制炎症细胞因子的表达，限制纤维化，并改善肌肉功能的恢复。我们得出结论，衰老导致肌肉中专门的促解决介质的局部生物合成不足，并且由于对肌肉功能恢复的积极影响而没有非甾体抗炎药对组织再生的负面影响，免疫调节剂可能是治疗老年人肌肉损伤和相关疼痛的有吸引力的新型治疗方法。
