Loss of FoxOs in muscle increases strength and mitochondrial function during aging.
Loss of FoxOs in muscle increases strength and mitochondrial function during aging.
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DOI：
10.1002/jcsm.13124
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发表时间：
2023-02
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影响因子：
--
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中科院分区：
文献类型：
--
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肌肉线粒体减少与衰老相关的肌无力和胰岛素抵抗有关。FoxO转录因子是胰岛素作用的靶点，FoxO的缺失改善了糖尿病中的线粒体功能。然而，蛋白质稳态和自噬的破坏是衰老的标志，并且FoxO在衰老肌肉中的慢性抑制的效果是未知的。这项研究调查了FoxOs在调节肌肉力量和线粒体功能随年龄增长的作用。我们测量了4.5个月（年轻）和22-24个月（老年）肌肉特异性FoxO 1/3/4三重KO（TKO）和同窝对照（Ctrl）小鼠的肌肉强度，横截面积，肌纤维类型，蛋白质合成/降解标志物，中央核，葡萄糖/胰岛素耐受性和线粒体生物能量学。与老年对照组和年轻组相比，老年TKO组的瘦体重增加了26-33%（P < 0.01）。通过胫骨前肌（TA）收缩的最大力测量的肌肉力量，老年对照组比年轻对照组低20%（P < 0.01），但老年TKO组没有降低。与对照组相比，年轻和老年TKO组的肌肉力量增加与肌肉重量增加18-48%相关（P < 0.01）。TA、比目鱼肌和跖肌的肌肉横截面分析显示，在年轻和老年TKO小鼠中，纤维尺寸分布增加，中央核增加2.5-10倍，没有肌肉损伤的组织学体征。在quad和TA中观察到Gadd 45 a和Ube 4a表达的年龄依赖性增加以及K48多聚泛素化蛋白的积累，但FoxO缺失阻止了这一点。与对照组相比，年轻和老年TKO肌肉显示出自噬通量的最小变化，并且没有自噬体的积累。与对照组相比，年轻和老年TKO中的力量增加与使用谷氨酸/苹果酸/琥珀酸的肌肉线粒体呼吸增加10-20%相关（P < 0.05）。与年轻对照相比，老年对照中的OXPHOS亚基表达和复合物I活性降低16-34%，但在老年TKO中被阻止。与年轻组相比，老年对照组和老年TKO组均显示出33%的葡萄糖耐量受损（P < 0.05），表明改善的强度和线粒体呼吸不是由于改善的呼吸。FoxO删除增加肌肉力量，即使在老化。FoxOs的缺失部分地通过轻度抑制萎缩途径（包括抑制Gadd 45 a和Ube 4a表达）来维持肌肉强度，而不会在肌肉中积累自噬体。在年轻和老年TKO中，FoxO的缺失也通过维持OXPHOS来改善线粒体功能。
Muscle mitochondrial decline is associated with aging‐related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age. We measured muscle strength, cross‐sectional area, muscle fibre‐type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5‐month (Young) and 22–24‐month‐old (Aged) muscle‐specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice. Lean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26–33% (P < 0.01). Muscle strength, measured by max force of tibialis anterior (TA) contraction, was 20% lower in Aged Ctrl compared with Young Ctrls (P < 0.01) but was not decreased in Aged TKOs. Increased muscle strength in Young and Aged TKO was associated with 18–48% increased muscle weights compared with Ctrls (P < 0.01). Muscle cross‐sectional analysis of TA, soleus, and plantaris revealed increases in fibre size distribution and a 2.5–10‐fold increase in central nuclei in Young and Aged TKO mice, without histologic signs of muscle damage. Age‐dependent increases in Gadd45a and Ube4a expression as well accumulation of K48 polyubiquitinated proteins were observed in quad and TA but were prevented by FoxO deletion. Young and Aged TKO muscle showed minimal changes in autophagy flux and no accumulation of autophagosomes compared with Ctrl groups. Increased strength in Young and Aged TKO was associated with a 10–20% increase in muscle mitochondrial respiration using glutamate/malate/succinate compared with controls (P < 0.05). OXPHOS subunit expression and complex I activity were decreased 16–34% in Aged Ctrl compared with Young Ctrl but were prevented in Aged TKO. Both Aged Ctrl and Aged TKO showed impaired glucose tolerance by 33% compared to young groups (P < 0.05) indicating improved strength and mitochondrial respiration are not due to improved glycemia. FoxO deletion increases muscle strength even during aging. Deletion of FoxOs maintains muscle strength in part by mild suppression of atrophic pathways, including inhibition of Gadd45a and Ube4a expression, without accumulation of autophagosomes in muscle. Deletion of FoxOs also improved mitochondrial function by maintenance of OXPHOS in both young and aged TKO.
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GADD45蛋白质：与衰老，寿命和与年龄相关的病理相关。
影响因子：
13.1
作者：
Moskalev, Alexey A.;Smit-McBride, Zeljka;Shaposhnikov, Mikhail V.;Plyusnina, Ekaterina N.;Zhavoronkov, Alex;Budovsky, Arie;Tacutu, Robi;Fraifeld, Vadim E.
通讯作者：
Fraifeld, Vadim E.
影响因子：
16.6
作者：
Milan, Giulia;Romanello, Vanina;Pescatore, Francesca;Armani, Andrea;Paik, Ji-Hye;Frasson, Laura;Seydel, Anke;Zhao, Jinghui;Abraham, Reimar;Goldberg, Alfred L.;Blaauw, Bert;DePinho, Ronald A.;Sandri, Marco
通讯作者：
Sandri, Marco
影响因子：
8.8
作者：
O'Neill BT;Lauritzen HP;Hirshman MF;Smyth G;Goodyear LJ;Kahn CR
通讯作者：
Kahn CR
DOI：
10.1074/jbc.m116.740308
发表时间：
2016-08-19
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bullard SA;Seo S;Schilling B;Dyle MC;Dierdorff JM;Ebert SM;DeLau AD;Gibson BW;Adams CM
通讯作者：
Adams CM
影响因子：
15.9
作者：
Bonnard, Charlotte;Durand, Annie;Rieusset, Jennifer
通讯作者：
Rieusset, Jennifer