DA-Raf and the MEK inhibitor trametinib reverse skeletal myocyte differentiation inhibition or muscle atrophy caused by myostatin and GDF11 through the non-Smad Ras?ERK pathway
DA-Raf and the MEK inhibitor trametinib reverse skeletal myocyte differentiation inhibition or muscle atrophy caused by myostatin and GDF11 through the non-Smad Ras?ERK pathway
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DA-Raf和MEK抑制剂曲美替尼通过非Smad Ras?ERK途径逆转肌生长抑制素和GDF11引起的骨骼肌细胞分化抑制或肌肉萎缩
DOI：
10.1093/jb/mvab116
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Endo Takeshi
中科院分区：
文献类型：
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作者：
Masuzawa Ryuichi;Takahashi Kazuya;Takano Kazunori;Nishino Ichizo;Sakai Toshiyuki;Endo Takeshi
肌肉抑制素(MSTN)和GDF11分别是年轻人肌肉萎缩和老年人骨骼肌减少的关键因素。这些转化生长因子-ERK超家族蛋白不仅能激活Smad信号，还能激活非Smad信号，包括RAS介导的β通路(Raf-MEK-ERK磷酸化级联反应)。尽管MSTN和GDF11已被证明通过Smad2/3介导的Akt抑制而诱导肌肉萎缩或肌萎缩症，但非Smad Ras-ERK通路在肌萎缩和肌萎缩症中的作用尚未得到很好的确定。我们在这里展示了MSTN和GDF11都阻止了骨骼肌细胞的分化，但MEK抑制剂U0126或曲美替尼恢复了MSTN或GDF11处理的肌细胞的分化。这些MEK抑制剂诱导RAS-ERK通路的显性-负性拮抗剂DA-Raf1(DA-Raf)的表达。外源性DA-Raf在MSTN或GDF11处理的心肌细胞中的表达恢复分化。此外，给老年小鼠服用曲美替尼可以增加肌纤维的大小或从肌肉萎缩中恢复。曲美替尼给药下调了这些肌肉中ERK的活性。这些结果表明，MSTN/GDF11诱导的RAS-ERK通路在抑制肌肉细胞分化和肌肉再生过程中发挥重要作用，从而导致肌肉萎缩。曲美替尼和类似批准的药物可能适用于治疗肌萎缩症或恶病质。
Myostatin (Mstn) and GDF11 are critical factors that are involved in muscle atrophy in the young and sarcopenia in the elderly, respectively. These TGF-β superfamily proteins activate not only Smad signalling but also non-Smad signalling including the Ras-mediated ERK pathway (Raf–MEK–ERK phosphorylation cascade). Although Mstn and GDF11 have been shown to induce muscle atrophy or sarcopenia by Smad2/3-mediated Akt inhibition, participation of the non-Smad Ras–ERK pathway in atrophy and sarcopenia has not been well determined. We show here that both Mstn and GDF11 prevented skeletal myocyte differentiation but that the MEK inhibitor U0126 or trametinib restored differentiation in Mstn- or GDF11-treated myocytes. These MEK inhibitors induced the expression of DA-Raf1 (DA-Raf), which is a dominant-negative antagonist of the Ras–ERK pathway. Exogenous expression of DA-Raf in Mstn- or GDF11-treated myocytes restored differentiation. Furthermore, administration of trametinib to aged mice resulted in an increase in myofiber size or recovery from muscle atrophy. The trametinib administration downregulated ERK activity in these muscles. These results imply that the Mstn/GDF11-induced Ras–ERK pathway plays critical roles in the inhibition of myocyte differentiation and muscle regeneration, which leads to muscle atrophy. Trametinib and similar approved drugs might be applicable to the treatment of muscle atrophy in sarcopenia or cachexia.