Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load.
Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load.
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DOI：
10.1038/s41598-021-83098-z
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发表时间：
2021-02-10
影响因子：
4.6
通讯作者：
Ogawa W
中科院分区：
文献类型：
--
作者：
Kuramoto N;Nomura K;Kohno D;Kitamura T;Karsenty G;Hosooka T;Ogawa W
磷脂酰肌醇3-激酶（PI 3 K）在蛋白质代谢和细胞生长中起重要作用。我们在此发现，骨骼肌特异性3′-磷酸肌醇依赖性激酶1（PDK 1）缺陷的小鼠（M-PDK 1 KO小鼠），PI 3 K信号通路的关键组分，表现出在静态条件下骨骼肌质量减少，以及机械负荷诱导的肌肉肥大受损。然而，机械负荷诱导的基因表达变化不受影响，核糖体蛋白S6激酶（S6 K）和机械负荷诱导的S6磷酸化在M-PDK 1 KO小鼠的骨骼肌中减弱，表明PDK 1调节肌肉肥大不是通过基因表达的变化，而是通过刺激激酶级联，如S6 K-S6轴，这在蛋白质合成中起着关键作用。β2-肾上腺素能受体（AR）激动剂克仑特罗（clenbuterol）可激活小鼠骨骼肌S6 K-S6轴，诱导肌肉肥大。克伦特罗的这些作用在M-PDK 1 KO小鼠中减弱，在骨骼肌特异性β2-AR缺乏的小鼠中，机械负荷诱导的S6 K-S6轴激活和肌肉肥大受到抑制。我们的研究结果表明，PDK 1调节骨骼肌质量在静态条件下，它有助于机械负荷诱导的肌肉肥大，至少部分通过介导信号从β2-AR。
Phosphatidylinositol 3-kinase (PI3K) plays an important role in protein metabolism and cell growth. We here show that mice (M-PDK1KO mice) with skeletal muscle–specific deficiency of 3′-phosphoinositide–dependent kinase 1 (PDK1), a key component of PI3K signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of mechanical load–induced muscle hypertrophy. Whereas mechanical load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by mechanical load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of kinase cascades such as the S6K-S6 axis, which plays a key role in protein synthesis. Administration of the β2-adrenergic receptor (AR) agonist clenbuterol activated the S6K-S6 axis in skeletal muscle and induced muscle hypertrophy in mice. These effects of clenbuterol were attenuated in M-PDK1KO mice, and mechanical load–induced activation of the S6K-S6 axis and muscle hypertrophy were inhibited in mice with skeletal muscle–specific deficiency of β2-AR. Our results suggest that PDK1 regulates skeletal muscle mass under the static condition and that it contributes to mechanical load–induced muscle hypertrophy, at least in part by mediating signaling from β2-AR.
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