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

Abstract

Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase of mitochondrial oxidative capacity to physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1+/−) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1+/− mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1+/− mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1+/− mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2 ± 0.2 vs. 7.1 ± 0.2, P=0.001), but not in cPDPK1+/− (6.2 ± 0.3 vs. 6.5 ± 0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7 ± 0.1 vs. 4.0 ± 0.1 mm, P=0.01) but not in cPDPK1+/− (3.8 ± 0.1 vs. 3.7 ± 0.1 mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6 ± 0.6 vs.16.1 ± 0.9, P=0.04; cPDPK1+/−: 12.4 ± 0.6 vs.15.9 ± 1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function.

Insulin Signaling and Heart Failure

“…However, combined deletion of IR and IGF-1receptors or IRS1 and IRS2 leads to catastrophic heart failure due in part to unrestrained autophagy, apoptosis and profound mitochondrial dysfunction 43, 150 . Similar phenotypes have been observed in animals with targeted loss of the phosphoinositide dependent protein kinase (pdpk1), which is required for IR or IGF-1R dependent activation of Akt 80 .…”

“…Thus mice with genetic deletion of the insulin receptor, or IRS proteins develop reduced mitochondrial oxidative capacity via partially understood mechanisms that may involve repressed expression of nuclear-encoded mitochondrial genes 43, 73, 76 . We have also shown that activation of PI3K signaling is responsible for increasing mitochondrial oxidative capacity in response to physiological cardiac hypertrophy 76, 79, 80 . However, this effect of PI3K appears to be independent of changes in Akt signaling and as will be discussed later, constitutive activation of Akt appears to repress mitochondrial oxidative capacity.…”

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

“…1B–D). Furthermore, exercise increased chamber diameter and wall thicknesses, improved indices of cardiac function (EDV, SV, and CO; Table S1), and activated the pro-hypertrophic signaling intermediate protein kinase B (AKT) 19-23 (Fig. 1E).…”

Metabolic regulation of myocardial adaptation to exercise.

“…20D), suggesting that their baseline cardiac phenotype is sufficient to meet the increased cardiovascular demands brought about by exercise. These results suggest that constitutively low glycolytic Because exercise could have beneficial effects on mitochondrial function, 39 we next posited that it might restore mitochondrial function in Glyco Lo hearts. In WT mice, exercise did not affect state 3 respiration in the presence of any substrate tested, and, in Glyco Lo mice, exercise did not reverse mitochondrial dysfunction caused by their metabolic phenotype (Fig.…”

“…Functioning downstream of PI3K, exercise training enhances the phosphorylation state of AKT at both the threonine 308 and 473 residues. 35,[39][40][41][42] This activation of AKT is required for the hypertrophic response as mice with genetic deletion are resistant to exercise-induced cardiac growth. 43 Interestingly, cardiac-specific overexpression of a constitutively active form of AKT, while initially promoting a physiologic form of hypertrophy, progressed to a pathologic form, suggesting that duration, and likely also intensity, determine the cardiac response to AKT signaling.…”