Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations. (December 2015)

• Record Type: Journal Article
• Authors: Noh, Junghyun; Wende, Adam R.; Olsen, Curtis D.; Kim, Bumjun; Bevins, Jack; Zhu, Yi; Zhang, Quan-Jiang; Riehle, Christian; Abel, E. Dale
• Is Part Of: Journal of molecular and cellular cardiology. Volume 89:Part B(2015)
• Page Start: 297
• Page End: 305
• Publication Date: 2015-12
• Subjects: Mitochondria -- PI3 kinase signaling -- Cardiac hypertrophy -- Exercise; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.10.015
• Languages: English
• ISSNs: 0022-2828

Abstract

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 in mitochondrial oxidative capacity following 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. Highlights: Exercise induces cardiac hypertrophy and mitochondrial oxidative capacity via PI3K-dependent but Akt-Independent pathways. PI3K activates PDPK1, but its role in the mitochondrial adaptations to exercise-induced hypertrophy is unknown. Mice with heterozygous deletion of Pdpk1 in cardiomyocytes (cPDPK1 +/− ) do not activate Akt or hypertrophy after exercise. Exercise increases mitochondrial oxidative capacity in cPDPK1 +/+ and cPDPK1 +/− hearts. Although exercise increases myocardial PI3K activity, the increase in mitochondrial oxidation occurs independently of PDPK1.