Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B

The oncogene p3k, coding for a constitutively active form of phosphatidylinositol 3-kinase (PI 3-kinase), strongly activates myogenic differentiation. Inhibition of endogenous PI 3-kinase activity with the specific inhibitor LY294002, or with dominant-negative mutants of PI 3-kinase, interferes with myotube formation and with the expression of muscle-specific proteins. Here we demonstrate that a downstream target of PI 3-kinase, serine-threonine kinase Akt, plays an important role in myogenic differentiation. Expression of constitutively active forms of Akt dramatically enhances myotube formation and expression of the muscle-specific proteins MyoD, creatine kinase, myosin heavy chain, and desmin. Transdominant negative forms of Akt inhibit myotube formation and the expression of muscle-specific proteins. The inhibition of myotube formation and the reduced expression of muscle-specific proteins caused by the PI 3-kinase inhibitor LY294002 are completely reversed by constitutively active forms of Akt. Wild-type cellular Akt effects a partial reversal of LY294002-induced inhibition of myogenic differentiation. This result suggests that Akt can substitute for PI 3-kinase in the stimulation of myogenesis; Akt may be an essential downstream component of PI 3-kinase-induced muscle differentiation.

编码组成型激活形式的磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase，PI 3-kinase）的癌基因p3k可强力激活肌源性分化。采用特异性抑制剂LY294002，或借助PI 3-激酶的显性负突变体，对内源PI 3-激酶活性进行抑制，会干扰肌管形成与肌肉特异性蛋白的表达。本研究证实，PI 3-激酶的下游靶标丝氨酸-苏氨酸激酶Akt在肌源性分化中发挥关键作用。组成型激活型Akt的表达可显著增强肌管形成，以及肌肉特异性蛋白MyoD、肌酸激酶、肌球蛋白重链和结蛋白的表达。反式显性负突变型Akt则会抑制肌管形成及肌肉特异性蛋白的表达。由PI 3-激酶抑制剂LY294002诱导产生的肌管形成抑制与肌肉特异性蛋白表达下调，可通过组成型激活型Akt完全逆转。野生型细胞Akt可部分逆转LY294002介导的肌源性分化抑制。上述结果表明，Akt可在肌发生刺激过程中替代PI 3-激酶；Akt或许是PI 3-激酶诱导肌肉分化过程中不可或缺的下游组分。