Effect of short-term or long-term Akt activation in cardiac muscle. (A) Short-term activation of Akt1 by physiological stimuli, such as insulin and IGF-1 signaling or exercise, promotes physiologic cardiac hypertrophy. Insulin and IGF-1 signaling is mediated in part via tyrosine phosphorylation (P) of IRS-1/2. Phosphorylated IRS-1/2 associates with and activates PI3K, which stimulates the generation of phosphoinositide-3,4,5 triphosphate and subsequently leads to the activation of Akt. Akt1 promotes physiologic hypertrophy via mTOR-mediated pathways. Short-term activation is associated with increased VEGF generation and release and may also protect against I/R injury. (B) Long-term, high-level Akt signaling is maladaptive. Downregulation of IRS-1/2 proteins occurs via mechanisms that involve increased proteasomal degradation. It is believed that increased serine phosphorylation of IRS-1/2 will promote this degradation. In addition, serine phosphorylation of IRS-1/2 limits its association with the insulin receptor, which further reduces the activation of PI3K. Reduced PI3K activation is associated with reduced recovery and increased tissue injury following I/R due to loss of PI3K-dependent but Akt-independent cardioprotective mechanisms. It is also possible that reduced IRS-1_mediated PI3K signaling may contribute to cardiac injury in patients with dilated cardiomyopathy. Long-term activation of Akt continues to promote cardiac hypertrophy. However, there is downregulation of VEGF expression, which leads to reduced angiogenesis. A mismatch between cardiomyocyte growth and blood vessel growth leads to cell death and fibrosis. Ub, ubiquitination.