MOTS-c reduces myostatin and muscle atrophy signaling
MOTS-c reduces myostatin and muscle atrophy signaling
复制标题
MOTS-c减少肌肉生长抑制素和肌肉萎缩信号传导
DOI：
10.1152/ajpendo.00275.2020
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发表时间：
2021-04-01
影响因子：
5.1
通讯作者：
Kim, Su-Jeong
中科院分区：
文献类型：
--
作者：
Kumagai, Hiroshi;Coelho, Ana Raquel;Kim, Su-Jeong
肥胖和2型糖尿病是代谢性疾病，通常与肌肉减少症和肌肉功能障碍有关。MOTS-c是一种线粒体衍生肽，充当全身激素，并与代谢稳态有关。虽然MOTS-c改善骨骼肌的胰岛素敏感性，但MOTS-c是否影响肌肉萎缩尚不清楚。肌生成抑制素是骨骼肌质量的负性调节因子，也是胰岛素抵抗诱导骨骼肌萎缩的可能介质之一。有趣的是，我们发现血浆MOTS-c水平与人类受试者中的肌肉生长抑制素水平呈负相关。我们进一步证明，MOTS-c防止软脂酸诱导的分化C2 C12肌管萎缩，而MOTS-c给药降低了饮食诱导的肥胖小鼠血浆中的肌肉生长抑制素水平。通过提高AKT磷酸化，MOTS-c抑制肌生长抑制素和其他肌肉萎缩基因FOXO 1的上游转录因子的活性。MOTS-c增加mTORC 2并抑制调节AKT磷酸化的PTEN活性。在更上游，MOTS-c增加CK 2活性，这导致PTEN抑制。这些结果表明，通过抑制肌肉生长抑制素，MOTS-c可能是一种潜在的治疗胰岛素抵抗诱导的骨骼肌萎缩以及其他肌肉萎缩表型，包括肌肉减少症。新&值得注意的是，MOTS-c，一种动物源性肽，通过减少肌肉生长抑制素的表达来减少高脂饮食诱导的肌肉萎缩信号传导。CK 2-PTEN-mTORC 2-AKT-FOXO 1通路在MOTS-c对肌生长抑制素表达的作用中起关键作用。
Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, whereas MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia.NEW & NOTEWORTHY MOTS-c, a mitochondrial-derived peptide reduces high-fat-diet-induced muscle atrophy signaling by reducing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways play key roles in MOTS-c action on myostatin expression.