Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle.
Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle.
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二甲双胍和亮氨酸增加卫星细胞和胶原重塑在废用和恢复老化肌肉。
DOI：
10.1096/fj.202100883r
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
Drummond MJ
中科院分区：
文献类型：
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作者：
Petrocelli JJ;Mahmassani ZS;Fix DK;Montgomery JA;Reidy PT;McKenzie AI;de Hart NM;Ferrara PJ;Kelley JJ;Eshima H;Funai K;Drummond MJ
随着年龄的增长，肌肉质量和力量在废用后的损失，随后是受损的肌肉恢复。二甲双胍和亮氨酸单独地在萎缩状况期间在骨骼肌中显示出积极作用，但尚未进行组合评估，也未测试作为增强衰老中废用性萎缩后肌肉恢复的补救措施。本研究的目的是确定二甲双胍和亮氨酸（MET+LEU）双重治疗是否会预防老年小鼠废用性萎缩和/或促进肌肉恢复，以及这些肌肉反应是否对应于卫星细胞和胶原蛋白重塑的变化。老年小鼠（22-24月龄）进行了14天的后肢卸载（HU），然后7或14天的重新加载（7或14天RL）。二甲双胍（MET）、亮氨酸（LEU）或MET+LEU通过饮用水给药，并与溶剂（标准饮用水）和动态基线（AMB）进行比较。我们观察到在HU期间，MET+LEU解决了由HU引起的全身握力和比目鱼肌比力下降。腓肠肌卫星细胞丰度增加MET+LEU治疗，但不改变废用或恢复条件下的肌肉大小。此外，MET+LEU治疗减轻了由HU引起的腓肠肌胶原积聚，并增加了由IV型胶原含量减少驱动的7和14 d RL期间的胶原周转。转录途径分析显示，MET+LEU改变了HU期间与炎症和肌生成相关的肌肉标志性途径。总之，二甲双胍和亮氨酸的双重治疗能够增加肌肉功能，卫星细胞含量，减少胶原蛋白积累，从而改善废用和衰老恢复期间的肌肉质量。
Loss of muscle mass and strength after disuse followed by impaired muscle recovery commonly occurs with aging. Metformin and leucine individually have shown positive effects in skeletal muscle during atrophy conditions but have not been evaluated in combination nor tested as a remedy to enhance muscle recovery following disuse atrophy in aging. The purpose of this study was to determine if a dual treatment of metformin and leucine (MET+LEU) would prevent disuse-induced atrophy and/or promote muscle recovery in aged mice and if these muscle responses correspond to changes in satellite cells and collagen remodeling. Aged mice (22–24 mo) underwent 14 days of hindlimb unloading (HU) followed by 7 or 14 days of reloading (7 or 14d RL). Metformin (MET), leucine (LEU), or MET+LEU was administered via drinking water and were compared to Vehicle (standard drinking water) and Ambulatory baseline (AMB). We observed that during HU, MET+LEU resolved whole body grip strength and soleus muscle specific force decrements caused by HU. Gastrocnemius satellite cell abundance was increased with MET+LEU treatment but did not alter muscle size during disuse or recovery conditions. Moreover, MET+LEU treatment alleviated gastrocnemius collagen accumulation caused by HU and increased collagen turnover during 7 and 14d RL driven by a decrease in collagen IV content. Transcriptional pathway analysis revealed that MET+LEU altered muscle hallmark pathways related to inflammation and myogenesis during HU. Together, the dual treatment of metformin and leucine was able to increase muscle function, satellite cell content, and reduce collagen accumulation, thus improving muscle quality during disuse and recovery in aging.