Chronic Inhibition of Pyruvate Dehydrogenase in Heart Triggers an Adaptive Metabolic Response

Abstract

Diabetic cardiac dysfunction is associated with decreased rates of myocardial glucose oxidation (GO) and increased fatty acid oxidation (FAO), a fuel shift that has been shown to sensitize the heart to ischemic insult and ventricular dysfunction. We sought to evaluate the metabolic and functional consequences of chronic suppression of GO in heart as modeled by transgenic mice with cardiac-specific overexpression of pyruvate dehydrogenase kinase 4 (myosin heavy chain (MHC)-PDK4 mice), an inhibitor of pyruvate dehydrogenase. Hearts of MHC-PDK4 mice were shown to exhibit an insulin-resistant substrate utilization profile, characterized by low GO rates and high FAO flux. Surprisingly, MHC-PDK4 mice were not sensitized to cardiac ischemia-reperfusion injury despite a fuel utilization pattern that phenocopied the diabetic heart. In addition, MHC-PDK4 mice were protected against high fat diet-induced myocyte lipid accumulation, likely related to increased capacity for FAO. The high rates of mitochondrial FAO in the MHC-PDK4 heart were related to heightened activity of the AMP-activated protein kinase, reduced levels of malonyl-CoA, and increased capacity for mitochondrial uncoupled respiration. The expression of the known AMP-activated protein kinase target, peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣), a master regulator of mitochondrial function and biogenesis, was also activated in the MHC-PDK4 heart. These results demonstrate that chronic activation of PDK4 triggers transcriptional and post-transcriptional mechanisms that re-program the heart for chronic high rates of FAO without the expected deleterious functional or metabolic consequences.The emerging pandemic of obesity is driving a dramatic increase in the incidence of type 2 diabetes mellitus and "metabolic syndrome" (1, 2). Diabetic individuals are more sensitive to co-morbidities known to cause heart failure, such as myocardial ischemic injury (3-5). The term "diabetic cardiomyopathy" has been coined to capture this unique condition. Although many factors certainly contribute, recent evidence suggests that diabetic cardiac dysfunction is driven at least in part by abnormalities in myocardial fuel metabolism (6 -8).The healthy adult mammalian heart exhibits energy substrate flexibility, utilizing a variety of energy substrates including fatty acids (FAs), 3 glucose, ketones, and lactate to yield ATP to meet the high energy demands of a constant pump (9, 10). In most conditions, FAs are the preferred substrate for myocardial ATP production, although a significant proportion of ATP is derived from glycolysis and glucose oxidation (GO) (8). The insulin-resistant diabetic heart loses this substrate flexibility due to reduced insulin responsive glucose uptake and oxidation, together with increased delivery of FAs, resulting in near complete reliance on fatty acid oxidation (FAO) for ATP production (7,11,12). GO is inhibited in the insulin-resistant heart at the step catalyzed by the pyruvate dehydrogenase complex, due in part to increased e...

Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

“…However, transcriptional analysis revealed that PDK4 was highly upregulated in hearts of HFD- fed WT animals ( Figure 1B and Supplemental Figure 9B). PDK4 is believed to function as a metabolic switch, shifting the cell toward FA utilization and away from glycolysis (5,16,(18)(19)(20). Loss of FoxO1 blunted PDK4 gene expression (Supplemental Figure 5 and Supplemental Figure 9B), a finding consistent with PDK4's being a known FoxO1 gene target (5,18,19).…”

“…Loss of FoxO1 blunted PDK4 gene expression (Supplemental Figure 5 and Supplemental Figure 9B), a finding consistent with PDK4's being a known FoxO1 gene target (5,18,19). However, it is unlikely that the entire cardiomyopathic response to HFD derives from PDK4 gene upregulation and resulting shifts in metabolic substrate utilization, as a cardiomyocyte-specific transgenic mouse line over-expressing PDK4 was not marked by apparent cardiomyopathy (18,20). FoxO1-dependent downregulation of IRS1 activity.…”

Regulation of the Transcription Factor EB-PGC1α Axis by Beclin-1 Controls Mitochondrial Quality and Cardiomyocyte Death under Stress

“…A total of 3 ϫ 10 4 cells were plated per well of a 96-well plate and transfected with the PGL3.Luc vector, carrying a 2,760-bp fragment of the human PPARGC1␣ promoter (for firefly luciferase expression), and the pRL-SV40 vector (for Renilla luciferase expression [31]) at a 100:1 ratio, using Lipofectamine 2000 (Invitrogen). Constructs coding for the human PPARGC1␣ promoter (GenBank accession number NG_028250.1) with individual mutations in the three CLEAR sites detected within (as depicted in Fig.…”

Improvement of myocardial lipid accumulation and prevention of PGC-1α induction by fenofibrate

“…For example, fenofibrate increases cardiac mitochondrial thioesterase I (MTE-I) mRNA, and reduced acyl-CoA oxidase (ACO) activity in diet-induced obese (DIO) mice (33,34). All the altered expression of these genes involved in cardiac mitochondrial function is coupled to a change in glucose utilization and fatty acid oxidation (35). Indeed, reduced ACO activity is linked to increased glucose oxidation and decreased fatty acid oxidation (34), and our studies also showed that downregulation of PGC-1α by fenofibrate is coupled to myocardial lipid accumulation.…”