4E-BP1/2 DKO mice are protected from aging-associated sarcopenia

 4E-BP1 and 4E-BP2 double knockout mice are protected from aging-associated sarcopenia

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|核心内容：

背景: Sarcopenia 是在衰老过程中发生的肌肉质量/功能的丧失。

机械性雷帕霉素靶蛋白(mTOR)活性与肌肉发育之间的联系已经被大量证实，但其下游靶蛋白在骨骼肌减少症发生中的作用却鲜为人知。

真核起始因子4E结合蛋白(4E-BPs)是 mTOR 的靶蛋白，它抑制 mRNA 翻译起始，参与多种生理过程的控制。

然而，它们在骨骼肌中的作用仍然知之甚少。

本研究的目的是评估4E-BP1和4E-BP2表达缺失如何影响老龄小鼠的骨骼肌功能和内环境稳定，并通过代谢组学和脂质体描述相关的代谢变化。

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方法: 采用24月龄野生型全身4E-BP1/4E-BP2双基因敲除(DKO)小鼠，测定其肌肉质量和功能。

采用 l-[ U-14C ]苯丙氨酸掺入法测定长伸肌的体外蛋白质稳态，让Metabolion,Inc 对骨骼肌进行代谢组学和脂质组学分析。

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结果：4E-BP1/2 DKO 小鼠肌肉量增加，与握力增加有关(p < 0.05)。

DKO 骨骼肌的蛋白质合成在基础(+102% ，p < 0.05) 和刺激(+ 65% ，p < 0.05) 条件下均较高。

骨骼肌的代谢组学和复杂的脂质分析揭示了氨基酸稳态，碳水化合物丰富度和脂质代谢的某些方面的巨大差异。

特别是，大多数游离氨基酸的水平在4E-BP1/2 DKO 肌肉里面较低（因为蛋白质合成消耗氨基酸）。

有趣的是，虽然葡萄糖水平没有变化，但等压化合物麦芽糖醇/乳糖醇(增加33倍，p < 0.01)和其他一些碳水化合物水平却发生了很大差异。

4E-BP1/2的缺失也导致中链酰基肉碱的积累，C2/C0酰基肉碱比值降低20% (p < 0.01) ，表明 β 氧化程度降低。

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结论：4E-BPs 缺失与骨骼肌能量代谢紊乱有关，对衰老小鼠骨骼肌质量和功能有积极影响。

他们还确定了4E-BPs 作为治疗骨骼肌减少症的潜在目标。

原文摘要：

 Background Sarcopenia is the loss of muscle mass/function that occurs during the aging process. The links between mechanistic target of rapamycin (mTOR) activity and muscle development are largely documented, but the role of its downstream targets in the development of sarcopenia is poorly understood. Eukaryotic initiation factor 4E-binding proteins (4E-BPs) are targets of mTOR that repress mRNA translation initiation and are involved in the control of several physiological processes. However, their role in skeletal muscle is still poorly understood. The goal of this study was to assess how loss of 4E-BP1 and 4E-BP2 expression impacts skeletal muscle function and homeostasis in aged mice and to characterize the associated metabolic changes by metabolomic and lipidomic profiling. Methods Twenty-four-month-old wild-type and whole body 4E-BP1/4E-BP2 double knockout (DKO) mice were used to measure muscle mass and function. Protein homeostasis was measured ex vivo in extensor digitorum longus by incorporation of L- [U-14C]phenylalanine, and metabolomic and lipidomic profiling of skeletal muscle was performed by Metabolon, Inc. Results The 4E-BP1/2 DKO mice exhibited an increase in muscle mass that was associated with increased grip strength (P < 0.05). Protein synthesis was higher under both basal (+102%, P < 0.05) and stimulated conditions (+65%, P < 0.05) in DKO skeletal muscle. Metabolomic and complex lipid analysis of skeletal muscle revealed robust differences pertaining to amino acid homeostasis, carbohydrate abundance, and certain aspects of lipid metabolism. In particular, levels of most free amino acids were lower within the 4E-BP1/2 DKO muscle. Interestingly, although glucose levels were unchanged, differences were observed in the isobaric compound maltitol/lactitol (33-fold increase, P < 0.01) and in several additional carbohydrate compounds. 4E-BP1/2 depletion also resulted in accumulation of medium-chain acylcarnitines and a 20% lower C2/C0 acylcarnitine ratio (P < 0.01) indicative of reduced β-oxidation. Conclusions Taken together, these findings demonstrate that deletion of 4E-BPs is associated with perturbed energy metabolism in skeletal muscle and could have beneficial effects on skeletal muscle mass and function in aging mice. They also identify 4E-BPs as potential targets for the treatment of sarcopenia. Keywords Anabolism; mTOR; Protein synthesis; Proteolysis; Skeletal muscle