Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail.
Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail.
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DOI：
10.18632/aging.204600
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发表时间：
2023-03-20
期刊：
影响因子：
5.2
通讯作者：
Drummond, Micah J.
中科院分区：
文献类型：
--
作者：
Petrocelli, Jonathan J.;de Hart, Naomi M. M. P.;Lang, Marisa J.;Yee, Elena M.;Ferrara, Patrick J.;Fix, Dennis K.;Chaix, Amandine;Funai, Katsuhiko;Drummond, Micah J.
衰老与骨骼肌内产生炎症产物的衰老细胞的积累相一致，称为衰老相关分泌表型，但衰老细胞与肌肉萎缩的关系尚不清楚。以前，我们发现二甲双胍+亮氨酸（MET + LEU）治疗对老年小鼠在废用性萎缩期间改善骨骼肌结构和功能具有协同作用。因此，该研究的目的是确定MET + LEU在体外表现出肌肉萎缩保护作用的机制，以及这是否通过细胞衰老发生。分化成肌管的C2C12成肌细胞用于确定萎缩期间的MET + LEU机制。此外，单独分离老年小鼠单肌纤维和老年人供体原代成肌细胞，以确定MET + LEU对肌细胞的翻译潜力。MET + LEU（25 + 125 μ M）处理增加了肌管分化并防止了肌管萎缩。低浓度（0.1 + 0.5 μ M）MET + LEU具有防止肌肉萎缩和增加与蛋白质合成相关的转录物和减少与蛋白质分解相关的转录物的独特作用。肌管萎缩导致蛋白质稳态失调，MET + LEU和单独蛋白酶体抑制剂（MG-132）可逆转这种失调。炎性和细胞衰老转录途径和相应的转录物在肌管萎缩后增加，但用MET + LEU处理逆转。达沙替尼+槲皮素（D + Q）与MET + LEU类似地防止肌管萎缩。最后，MET + LEU防止肌肉萎缩的替代体外模型以及老化肌纤维中肌管尺寸的损失，而在人原代肌管中，MET + LEU防止肌核融合的减少。这些数据支持MET + LEU具有骨骼肌细胞自主特性，可通过逆转衰老和改善蛋白质稳态来预防萎缩。
Aging coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence-associated secretory phenotype, but the relationship of senescent cells to muscle atrophy is unclear. Previously, we found that a metformin + leucine (MET+LEU) treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the study’s purpose was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during atrophy. Additionally, aged mouse single myofibers and older human donor primary myoblasts were individually isolated to determine the translational potential of MET+LEU on muscle cells. MET+LEU (25 + 125 μM) treatment increased myotube differentiation and prevented myotube atrophy. Low concentration (0.1 + 0.5 μM) MET+LEU had unique effects to prevent muscle atrophy and increase transcripts related to protein synthesis and decrease transcripts related to protein breakdown. Myotube atrophy resulted in dysregulated proteostasis that was reversed with MET+LEU and individually with proteasome inhibition (MG-132). Inflammatory and cellular senescence transcriptional pathways and respective transcripts were increased following myotube atrophy yet reversed with MET+LEU treatment. Dasatinib + quercetin (D+Q) senolytic prevented myotube atrophy similar to MET+LEU. Finally, MET+LEU prevented loss in myotube size in alternate in vitro models of muscle atrophy as well as in aged myofibers while, in human primary myotubes, MET+LEU prevented reductions in myonuclei fusion. These data support that MET+LEU has skeletal muscle cell-autonomous properties to prevent atrophy by reversing senescence and improving proteostasis.
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影响因子：
8.1
作者：
Englund, Davis A.;Jolliffe, Alyssa;Aversa, Zaira;Zhang, Xu;Sturmlechner, Ines;Sakamoto, Ayumi E.;Zeidler, Julianna D.;Warner, Gina M.;McNinch, Colton;White, Thomas A.;Chini, Eduardo N.;Baker, Darren J.;van Deursen, Jan M.;LeBrasseur, Nathan K.
通讯作者：
LeBrasseur, Nathan K.
亮氨酸，二甲双胍和西地那非的组合可治疗小鼠的非酒精性脂肪肝病和脂肪性肝炎。
影响因子：
1.8
作者：
Bruckbauer A;Banerjee J;Fu L;Li F;Cao Q;Cui X;Wu R;Shi H;Xue B;Zemel MB
通讯作者：
Zemel MB
影响因子：
82.9
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
DOI：
10.1097/mco.0b013e3282fa17fb
发表时间：
2008-05-01
影响因子：
3.1
作者：
Drummond, Micah J.;Rasmussen, Blake B.
通讯作者：
Rasmussen, Blake B.
影响因子：
3.2
作者：
Dias, Raquel da Luz;Basso, Bruno;de Oliveira, Jarbas Rodrigues
通讯作者：
de Oliveira, Jarbas Rodrigues