Disassociation of insulin action and Akt/FOXO signaling in skeletal muscle of older Akt-deficient mice.

The purpose of the present study was to determine the effect of Akt gene ablation on Akt/Forkhead Box O (FOXO) signaling and atrogene expression. This was accomplished by studying wild-type (WT) and isoform-specific Akt knockout (Akt1(-/-) and Akt2(-/-)) mice. The ability of insulin to promote Akt phosphorylation on Ser(473) was significantly lower in extensor digitorum longus (EDL) and soleus muscles from Akt1(-/-) and Akt2(-/-) mice compared with WT mice. Total Akt1 protein levels were significantly lower in EDL muscles of Akt2(-/-) mice compared with WT mice, a process that appears to be posttranscriptionally regulated as Akt1 mRNA levels were unchanged. The loss of Akt1 protein in EDL muscles of Akt2(-/-) mice does not appear to be due to insulin resistance because 4 mo of a high-fat diet failed to reduce Akt1 protein levels in muscles of WT mice. Although FOXO3a phosphorylation and atrogin-1 expression were unaltered in muscles of Akt1(-/-) and Akt2(-/-) mice, the expression of the atrogenes Bnip3 and gabarapl were significantly elevated in muscles of both Akt1 and Akt2 knockout mice. Finally, the expression of striated activator of Rho signaling was significantly increased in muscles of Akt2(-/-) mice compared with Akt1(-/-) and WT mice. Our results demonstrate that the ablation of Akt isoforms disassociates insulin action and Akt/FOXO signaling to atrogenes.