Abstract 773: Impact of PGC-1 beta Deletion on Contractile, Metabolic and Transcriptional Responses of the Heart to Pressure Overload Hypertrophy
The transcriptional coactivators PGC1-alpha and beta regulate mitochondrial function and biogenesis. Their respective roles in metabolic adaptations to cardiac hypertrophy are unknown. We evaluated cardiac function, substrate utilization and mitochondrial gene expression in hearts of mice with germline deletion of PGC1-beta (PGC1b). At baseline, in vivo and ex vivo cardiac function was normal. In isolated working PGC1-b KO hearts, glucose and FA oxidation rates were increased by 21% and 55% respectively (p<0.01). 21-days following transverse aortic banding (TAB), control (WT) and KO developed equivalent LV hypertrophy and maintained contractile function. Relative to shams, glycolysis (GLYCOL) and glucose oxidation (GOX) increased by 15% and 18% respectively after TAB (p<0.05) in WT hearts. In contrast, GLYCOL and GOX declined in banded KO mice by 26% and 25% respectively (p<0.001). GOX (nmol/min/g dwt) was 628±33(WT) vs. 471±34(KO) and GLYCOL was 6020±290(WT) vs. 4993±213(KO) following TAB (p<0.001). FA OX declined by 16% in KO and 13% in WT after TAB. MVO2 was 25% higher in banded KO (p<0.02) resulting in decreased cardiac efficiency of 5.3±0.5% vs. 9.6±0.6% in banded WT (p<0.003). In sham PGC1-b KO, PGC1-alpha expression was unchanged. Expression of OXPHOS genes were uniformly reduced however (by 25–40%) but most FAO genes were unchanged except for MCAD, Acyl CoA thioesterase (Acate) and carnitine acyl/carnitine translocase (reduced by 12–20%). PGC1-alpha, FAO and OXPHOS gene expression were uniformly reduced by TAB in WT mice (by 20–50%). OXPHOS genes were already lower in PGC1-b KO mice and with the exception of cox5b, cytochrome oxidase and Ndufa9 whose expression fell further with TAB, were relatively unaffected by cardiac hypertrophy. A subset of FAO genes declined with TAB in KO mice (PGC1-alpha, UCP2, UCP3 and Hadh), but others (PPARa, FABP, FACL2 Acate 2and 3) did not. Taken together, these data define a unique role for PGC1-b in increasing glucose metabolism and maintaining cardiac efficiency following pressure overload, identify a specific subset of FAO genes whose regulation during pressure overload require PGC1-b and confirm an important role for PGC1-b in the basal expression of OXPHOS genes.