BackgroundSarcopenia is characterized by loss of skeletal muscle mass and function, and is a major risk factor for disability and independence in the elderly. Effective medication is not available. Dietary restriction (DR) has been found to attenuate aging and aging‐related diseases, including sarcopenia, but the mechanism of both DR and sarcopenia are incompletely understood.MethodsIn this study, mice body weight, fore and all limb grip strength, and motor learning and coordination performance were first analysed to evaluate the DR effects on muscle functioning. Liquid chromatography–mass spectrometry (LC–MS) was utilized for the metabolomics study of the DR effects on sarcopenia in progeroid DNA repair‐deficient Ercc1∆/− and Xpg−/− mice, to identify potential biomarkers for attenuation of sarcopenia.ResultsMuscle mass was significantly (P < 0.05) decreased (13–20%) by DR; however, the muscle quality was improved with retained fore limbs and all limbs grip strength in Ercc1∆/− and Xpg−/− mice. The LC–MS results revealed that metabolites and pathways related to oxidative‐stress, that is, GSSG/GSH (P < 0.01); inflammation, that is, 9‐HODE, 11‐HETE (P < 0.05), PGE2, PGD2, and TXB2 (P < 0.01); and muscle growth (PGF2α) (P < 0.01) and regeneration stimulation (PGE2) (P < 0.05) are significantly downregulated by DR. On the other hand, anti‐inflammatory indicator and several related metabolites, that is, β‐hydroxybutyrate (P < 0.01), 14,15‐DiHETE (P < 0.0001), 8,9‐EET, 12,13‐DiHODE, and PGF1 (P < 0.05); consumption of sources of energy (i.e., muscle and liver glycogen); and energy production pathways, that is, glycolysis (glucose, glucose‐6‐P, fructose‐6‐P) (P < 0.01), tricarboxylic acid cycle (succinyl‐CoA, malate) (P < 0.001), and gluconeogenesis‐related metabolite, alanine (P < 0.01), are significantly upregulated by DR. The notably (P < 0.01) down‐modulated muscle growth (PGF2α) and regeneration (PGE2) stimulation metabolite and the increased consumption of glycogen in muscle and liver may be related to the significantly (P < 0.01) lower body weight and muscle mass by DR. The downregulated oxidative stress, pro‐inflammatory mediators, and upregulated anti‐inflammatory metabolites resulted in a lower energy expenditure, which contributed to enhanced muscle quality together with upregulated energy production pathways by DR. The improved muscle quality may explain why grip strength is maintained and motor coordination and learning performance are improved by DR in Ercc1∆/− and Xpg−/− mice.ConclusionsThis study provides fundamental supporting information on biomarkers and pathways related to the attenuation of sarcopenia, which might facilitate its diagnosis, prevention, and clinical therapy.

中文翻译：

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饮食限制诱导的早衰 DNA 修复缺陷小鼠肌肉减少症减弱的代谢组学分析

背景肌肉减少症的特点是骨骼肌质量和功能丧失，是老年人残疾和独立的主要危险因素。没有有效的药物治疗。研究发现，饮食限制 (DR) 可减轻衰老和衰老相关疾病，包括肌肉减少症，但 DR 和肌肉减少症的机制尚不完全清楚。 方法在本研究中，小鼠体重、前肢和四肢握力以及运动学习首先分析协调表现，以评估 DR 对肌肉功能的影响。利用液相色谱-质谱 (LC-MS) 进行 DR 对早衰 DNA 修复缺陷型肌肉减少症的影响的代谢组学研究埃克1Δ/-和XPG−/−小鼠，以确定减轻肌肉减少症的潜在生物标志物。结果肌肉质量显着（磷< 0.05) 因 DR 降低 (13–20%)；然而，通过保留前肢和所有肢体的握力，肌肉质量得到了改善埃克1Δ/-和XPG−/−老鼠。 LC-MS 结果显示，与氧化应激相关的代谢物和途径，即 GSSG/GSH（磷< 0.01);炎症，即 9-HODE、11-HETE（磷< 0.05), 前列腺素E2, 胚胎植入前诊断2，和TXB2（磷< 0.01);和肌肉生长（PGF2α) (磷< 0.01) 和再生刺激 (PGE2) (磷< 0.05) 被 DR 显着下调。另一方面，抗炎指标和几种相关代谢物，即β-羟基丁酸（磷< 0.01), 14,15-DiHETE (磷< 0.0001)、8,9-EET、12,13-DiHODE 和 PGF1（磷< 0.05);能量来源的消耗（即肌肉和肝糖原）；和能量产生途径，即糖酵解（葡萄糖、葡萄糖-6-P、果糖-6-P）（磷< 0.01)，三羧酸循环（琥珀酰辅酶A，苹果酸）（磷< 0.001），以及糖异生相关代谢物丙氨酸（磷< 0.01)，被 DR 显着上调。值得注意的是（磷< 0.01) 下调肌肉生长 (PGF2α）和再生（PGE2）刺激代谢以及肌肉和肝脏中糖原消耗的增加可能与显着（磷< 0.01) DR 降低体重和肌肉质量。下调的氧化应激、促炎介质和上调的抗炎代谢物导致能量消耗降低，这有助于增强肌肉质量以及 DR 上调的能量产生途径。肌肉质量的提高可以解释为什么 DR 可以保持握力并提高运动协调性和学习表现埃克1Δ/−和XPG−/−结论这项研究提供了与肌少症减弱相关的生物标志物和途径的基本支持信息，这可能有助于其诊断、预防和临床治疗。