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 α 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 Ser, and protein expression of α subunit. Furthermore, IGF-1 treatment increased phosphorylation of IRS-1 on Tyr, Akt on Ser, PDK-1 on Ser, mTOR on Ser and Ser, and S6K on Thr/Ser. The concentration of IGF-1 in serum positively correlates with Na/K-ATPase activity and the phosphorylated form of mTOR (Ser), while Na/K-ATPase activity positively correlates with the phosphorylated form of IRS-1 (Tyr) and mTOR (Ser).

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.