The involvement of Akt, mTOR, and S6K in the in vivo effect of IGF-1 on the regulation of rat cardiac Na + /K + -ATPase.

BACKGROUND: We previously demonstrated that insulin-like growth factor-1 (IGF-1) regulates sodium/potassium adenosine triphosphatase (Na+ /K+ -ATPase) in vascular smooth muscle cells (VSMC) via phosphatidylinositol-3 kinase (PI3K). Taking into account that others' work show that IGF-1 activates the PI3K/protein kinase B (Akt) signaling pathway in many different cells, we here further questioned if the Akt/mammalian target of rapamycin (mTOR)/ribosomal protein p70 S6 kinase (S6K) pathway stimulates Na+ /K+ -ATPase, an essential protein for maintaining normal heart function.

METHODS AND RESULTS: There were 14 adult male Wistar rats, half of whom received bolus injections of IGF-1 (50 μg/kg) for 24 h. We evaluated cardiac Na+ /K+ -ATPase expression, activity, and serum IGF-1 levels. Additionally, we examined the phosphorylated forms of the following proteins: insulin receptor substrate (IRS), phosphoinositide-dependent kinase-1 (PDK-1), Akt, mTOR, S6K, and α subunit of Na+ /K+ -ATPase. Additionally, the mRNA expression of the Na+ /K+ -ATPase α1 subunit was evaluated. Treatment with IGF-1 increases levels of serum IGF-1 and stimulates Na+ /K+ -ATPase activity, phosphorylation of α subunit of Na+ /K+ -ATPase on Ser23 , and protein expression of α2 subunit. Furthermore, IGF-1 treatment increased phosphorylation of IRS-1 on Tyr1222 , Akt on Ser473 , PDK-1 on Ser241 , mTOR on Ser2481 and Ser2448 , and S6K on Thr421 /Ser424 . The concentration of IGF-1 in serum positively correlates with Na+ /K+ -ATPase activity and the phosphorylated form of mTOR (Ser2448 ), while Na+ /K+ -ATPase activity positively correlates with the phosphorylated form of IRS-1 (Tyr1222 ) and mTOR (Ser2448 ).

CONCLUSION: These results indicate that the Akt/mTOR/S6K signalling pathway may be involved in the IGF-1 regulating cardiac Na+ /K+ -ATPase expression and activity.