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Role of Phosphoinositide 3-OH Kinase p110β in Skeletal Myogenesis

机译：磷酸肌醇3-OH激酶p110β在骨骼肌发生中的作用

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Phosphoinositide 3-OH kinase (PI3K) regulates a number of developmental and physiologic processes in skeletal muscle; however, the contributions of individual PI3K p110 catalytic subunits to these processes are not well-defined. To address this question, we investigated the role of the 110-kDa PI3K catalytic subunit β (p110β) in myogenesis and metabolism. In C2C12 cells, pharmacological inhibition of p110β delayed differentiation. We next generated mice with conditional deletion of p110β in skeletal muscle (p110β muscle knockout [p110β-mKO] mice). While young p110β-mKO mice possessed a lower quadriceps mass and exhibited less strength than control littermates, no differences in muscle mass or strength were observed between genotypes in old mice. However, old p110β-mKO mice were less glucose tolerant than old control mice. Overexpression of p110β accelerated differentiation in C2C12 cells and primary human myoblasts through an Akt-dependent mechanism, while expression of kinase-inactive p110β had the opposite effect. p110β overexpression was unable to promote myoblast differentiation under conditions of p110α inhibition, but expression of p110α was able to promote differentiation under conditions of p110β inhibition. These findings reveal a role for p110β during myogenesis and demonstrate that long-term reduction of skeletal muscle p110β impairs whole-body glucose tolerance without affecting skeletal muscle size or strength in old mice.
机译：磷酸肌醇3-OH激酶（PI3K）调节骨骼肌中的许多发育和生理过程。然而，单个PI3K p110催化亚基对这些过程的贡献尚不清楚。为了解决这个问题，我们研究了110 kDa PI3K催化亚基β（p110β）在肌发生和代谢中的作用。在C2C12细胞中，p110β的药理抑制作用可延迟分化。接下来，我们生成了骨骼肌中p110β有条件缺失的小鼠（p110β肌肉敲除[p110β-mKO]小鼠）。虽然年轻的p110β-mKO小鼠的四头肌重量较小，并且其强度比同窝同窝小，但在老年小鼠的基因型之间未观察到肌肉质量或强度的差异。但是，老的p110β-mKO小鼠比老的对照小鼠对葡萄糖的耐受性差。 p110β的过表达通过Akt依赖性机制促进了C2C12细胞和原代人成肌细胞的分化，而激酶失活的p110β的表达则相反。在p110α抑制的条件下，p110β的过表达不能促进成肌细胞的分化，但是在p110β抑制的条件下，p110α的表达能够促进分化。这些发现揭示了p110β在肌生成过程中的作用，并证明骨骼肌p110β的长期降低会损害全身葡萄糖耐受性，而不会影响老年小鼠的骨骼肌大小或强度。

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