Abstract 1298: PI3-Kinase Regulates Myocardial Mitochondrial Mass and Oxidative Capacity via Akt-Independent Signaling Pathways
Phosphoinositide-3-kinase (PI3K) plays a critical role in physiologic cardiac hypertrophy. We previously reported that PI3K regulates myocardial fatty acid metabolism (mFAO), and that chronic activation of cardiac Akt leads to diminished mitochondrial oxidative capacity whereas mFAO is unchanged in hearts from germline Akt1 and Akt2 null mice. To test the hypothesis that PI3K regulates mitochondrial oxidative capacity independently of Akt signaling, we crossed mice with cardiac restricted expression of the inter-SH2 fusion of p110, which maintains PI3K in a constitutively activated state (caPI3K) with mice expressing a kinase dead Akt1 (K179M) (dnAkt) to produce double transgenic animals (DTG) and determined 1) heart weight to body weight (HW/BW) ratios, 2) mitochondrial respiration (MITO RESP) in saponin-permeabilized cardiac fibers treated with palmitoyl-carnitine (PC) as substrate and 3) beta-oxidation and citrate synthase (CS) enzyme activities. Although HW/BW was increased in DTG compared to dnAkt and WT controls (4.58 ± 0.07 vs. 4.16 ± 0.13 and 4.08 ± 0.08, respectively p<0.01), HW/BW was attenuated in DTG compared to caPI3K (4.94 ± 0.06, p<0.01 vs. DTG). State 3 of MITO RESP with PC (nmol/min/mg dw) was unchanged in dnAkt fibers vs. WT controls (15.4 ± 0.6 vs. 15.8 ± 0.5), but MITO RESP was increased in caPI3K and DTG fibers (17.4 ± 0.6 and 17.8 ± 0.7, respectively p<0.05 vs. WT). 3-hydroxyacyl-CoA dehydrogenase (HADH) enzyme activity was increased 19% and 32% in caPI3K and DTG, respectively (p<0.05) but was unchanged in dnAkt. Interestingly, CS activity was increased by 13%, 17%, and 14% in dnAkt, caPI3K, and DTG hearts, respectively (p<0.01 vs. WT controls). In summary, impaired cardiac Akt signaling attenuated PI3K-induced hypertrophy, but mitochondrial respiratory capacity and HADH and CS enzyme activities remained increased. Thus PI3K signaling is an important regulator of myocardial mitochondrial mass and FA oxidative capacity, and this regulation is likely mediated by PI3K or phosphoinositide-dependent signaling pathways other than Akt.