Sarcopenia is a progressive and generalized age-related skeletal muscle (SkM) disorder characterized by the accelerated loss of muscle mass (atrophy) and function. SkM atrophy is associated with increased incidence of falls, functional decline, frailty and mortality. In its early stage, SkM atrophy is associated with increased pro-inflammatory cytokine levels and proteasome-mediated protein degradation. These processes also link to the activation of atrophy associated factors and signaling pathways for which, there is a lack of approved pharmacotherapies. The objective of this study, was to characterize the capacity of the flavanol (+)-epicatechin (+Epi) to favorably modulate SkM mass and function in a rat model of aging induced sarcopenia and profile candidate mechanisms. Using 23 month old male Sprague-Dawley rats, an 8 weeks oral administration of the +Epi (1 mg per kg per day in water by gavage) was implemented while control rats only received water. SkM strength (grip), treadmill endurance, muscle mass, myofiber area, creatine kinase, lactate dehydrogenase, troponin, α-actin, tumor necrosis factor (TNF)-α and atrophy related endpoints (follistatin, myostatin, NFκB, MuRF 1, atrogin 1) were quantified in plasma and/or gastrocnemius. We also evaluated effects on insulin growth factor (IGF)-1 levels and downstream signaling (AKT/mTORC1). Treatment of aged rats with +Epi, led to significant increases in front paw grip strength, treadmill time and SkM mass vs. controls as well as beneficial changes in makers of myofiber integrity. Treatment significantly reversed adverse changes in plasma and/or SkM TNF-α, IGF-1, atrophy and protein synthesis related endpoints vs. controls. In conclusion, +Epi has the capacity to reverse sarcopenia associated detrimental changes in regulatory pathways leading to improved SkM mass and function. Given these results and its recognized safety and tolerance profile, +Epi warrants consideration for clinical trials.

中文翻译：

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(+)-表儿茶素在衰老引起的肌肉萎缩的啮齿动物模型中的恢复作用：潜在机制

肌肉减少症是一种进行性、全身性的与年龄相关的骨骼肌 (SkM) 疾病，其特征是肌肉质量（萎缩）和功能加速丧失。SkM 萎缩与跌倒、功能衰退、虚弱和死亡率增加的发生率相关。在早期阶段，SkM 萎缩与促炎细胞因子水平增加和蛋白酶体介导的蛋白质降解有关。这些过程还与萎缩相关因子和信号传导途径的激活有关，但目前缺乏批准的药物疗法。本研究的目的是表征黄烷醇 (+)-表儿茶素 (+Epi) 在衰老诱发的肌肉减少症大鼠模型中有利地调节 SkM 质量和功能的能力，并分析候选机制。使用 23 个月大的雄性 Sprague-Dawley 大鼠，口服+Epi（每天 1 mg/kg，水中灌胃）8 周，而对照大鼠仅接受水。SkM 力量（握力）、跑步机耐力、肌肉质量、肌纤维面积、肌酸激酶、乳酸脱氢酶、肌钙蛋白、α-肌动蛋白、肿瘤坏死因子 (TNF)-α 和萎缩相关终点（卵泡抑素、肌生长抑制素、NFκB、MuRF 1、atrogin） 1) 在血浆和/或腓肠肌中进行定量。我们还评估了对胰岛素生长因子 (IGF)-1 水平和下游信号传导 (AKT/mTORC1) 的影响。用+Epi治疗老年大鼠，与对照组相比，前爪握力、跑步时间和SkM质量显着增加，并且肌纤维完整性发生有益变化。与对照组相比，治疗显着逆转了血浆和/或 SkM TNF-α、IGF-1、萎缩和蛋白质合成相关终点的不利变化。总之，+Epi 有能力逆转肌肉减少症相关的调节途径的有害变化，从而改善 SkM 质量和功能。鉴于这些结果及其公认的安全性和耐受性，+Epi 值得考虑进行临床试验。