Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

Abstract

h Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor ␣ (PPAR␣)/PGC-1␣ and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1␣. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. Mitochondrial metabolism of fatty acids (FA) and, to a lesser extent, glucose, lactate, and ketone bodies generates ATP to sustain cardiac contractile function. Myocardial metabolism is a flexible process that adapts to various stimuli, including substrate supply, hormonal and growth factor stimulation, and cardiac hypertrophy (LVH). In physiological hypertrophy (e.g., after exercise), FA and glucose oxidation are both increased in the heart (1). Pathological hypertrophy, as occurs following pressure overload leading to heart failure, is associated with increased glucose utilization but mitochondrial dysfunction (2). Although increased glucose utilization may be an adaptive response, persistent pathological stimulation ultimately limits cardiac metabolic flexibility, which may contribute to heart failure. Acute activation of Akt in the heart in vitro or in vivo increases glucose uptake and protects the heart from ischemia/reperfusion injury (3, 4). In contrast, long-term activation of Akt results in cardiac hypertrophy (LVH) that is associated with a range of functional outcomes from increased contractility to heart failure, due in part to the level of overexpression or subcellular localization of Akt (5, 6). Persistent Akt signaling may be deleterious to the heart due to feedback inhibition of insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K) signaling or GLUT4-mediated glucose uptake (7-9). Although short-term activation of Akt may induce LVH with preserved cardiac function, sustained Akt activation precipitates heart failure due in part to a mismatch between cardiac hypertrophy and angiogenesis (7, 10). Cardiac failure is also associated with significant changes in myocardial substrate energy metabolism (1). Thus, th...

Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations

“…However, inhibition of cardiac Akt signaling did not diminish mitochondrial respiration or FAO enzyme activity when PI3K was activated by exercise training. Additionally, attenuation of Akt signaling in hearts of animals expressing a kinase inactive Akt, increased ATP production [6], whereas constitutive activation of Akt repressed mitochondrial function [7]. Thus the effect of PI3K activation on mitochondrial function in physiological cardiac hypertrophy is independent of Akt activity.…”

“…Others and we have shown that whereas activation of class 1A PI3K and Akt-mediated signal transduction pathways are required for physiological cardiac growth [2–6] the mitochondrial adaptations while dependent on PI3K are independent of Akt signaling [6]. Moreover, constitutive activation of Akt signaling leads to repression of mitochondrial oxidative capacity [7]. Upstream of PI3K, insulin receptor, insulin-like growth factor 1 (IGF-1) receptor signaling and signaling via the insulin receptor substrates 1 and 2 (IRS1, 2) are also required for activating PI3K-signaling and the mitochondrial adaptations that accompany exercise-induced cardiac hypertrophy [8–10].…”

Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis

“…For rapamycin treatments, mice were injected i.p. with rapamycin (2 mg/kg/d) or vehicle (0.2% sodium carboxymethylcellulose, 0.25% polysorbate-80 in water) daily for up to 2 weeks as previously described (41). For MG132 treatments, mice were injected i.p.…”

Increased Protein Tyrosine Phosphatase 1B (PTP1B) Activity and Cardiac Insulin Resistance Precede Mitochondrial and Contractile Dysfunction in Pressure‐Overloaded Hearts

“…Because the changes in Akt phosphorylation are in concert with those in heart weight (rapid gain from 2 to 10 weeks; Table 1), Akt appears to be primarily regulated by hypertrophic signals in our model. Of note, recent evidence suggests that chronic activation of Akt may affect mitochondrial biogenesis and function 37. Thus, it is possible that the prolonged activation of Akt also contributed to mitochondrial dysfunction.…”