Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the Study of Muscle, Mobility and Aging (SOMMA).
Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the Study of Muscle, Mobility and Aging (SOMMA).
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在肌肉、活动性和衰老研究 (SOMMA) 中，老年人骨骼肌中的自噬基因表达与身体表现、肌肉体积和线粒体功能相关。
DOI：
10.1101/2023.11.04.23297979
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Esser,K
中科院分区：
文献类型：
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作者：
Coen,PaulM;Huo,Zhiguang;Tranah,GregoryJ;Barnes,HaleyN;Cawthon,PeggyM;Hepple,RussellT;Toledo,FredericoGS;Evans,DanielS;Fernández,OlayaSantiago;Cuervo,AnaMaria;Kritchevsky,StevenB;Newman,AnneB;Cummings,StevenR;Esser,K
自噬对于蛋白质稳态、能量平衡和细胞防御是必不可少的，并且是衰老的关键途径。确定骨骼肌中自噬基因表达模式与体能结果之间的关联将进一步加深我们对蛋白质稳态和健康衰老相关机制的认识。肌肉活检是从肌肉、运动和衰老研究（SOMMA）的参与者中获得的。对575名参与者进行了RNA测序，并确定了与自噬调控、线粒体自噬和mTOR/上游通路相关的281个基因的表达。基因表达和结果之间的关联，包括肌纤维束中的线粒体呼吸（MAX OXPHOS），体能（VO 2峰值，400米步行速度和腿部力量），和大腿肌肉体积，使用负二项回归模型进行了确定。对于自噬，关键的转录调节因子包括TFE 3和NF κ B相关基因（RELA，RELB和NF κ B 1）与结果呈负相关。相反，氧化代谢的调节剂，也促进整体自噬，线粒体自噬和pexophagy（PPARGC 1A，PPARA和EPAS 1）与多种结果呈正相关。与此一致，一些线粒体自噬、融合和裂变相关基因（NIPSNAP 2、DNM 1 L和OPA 1）也与结局呈正相关。对于mTOR通路和相关基因，WDR 59和WDR 24（GATOR 2复合物（mTORC 1的间接抑制剂）的两个亚基）以及AMPK的调节亚基PRKAG 3的表达与多种结局呈负相关。我们的研究确定了自噬和选择性自噬，例如与老年人的身体表现，肌肉体积和线粒体功能相关的人类骨骼肌中的线粒体自噬基因表达模式，这可能导致目标识别以保持移动性和独立性。
Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB‐related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission‐related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.