Objectives: Insulin Resistance (IR) and/or mitochondrial dysfunction may coexist in failing hearts. We hypothesized that IR precedes the onset of mitochondrial dysfunction during the development of pressure overload heart failure.
Objectives: Pressure overload induced heart failure is correlated with significant impairment in mitochondrial function. In normoxia >95% of the ATP is produced there. In heart muscle, two types of mitochondria exist. Subsarcolemmal mitochondria (SSM), presumably providing ATP for basic cell function, and interfibrillar mitochondria (IFM), presumably providing energy for the contractile apparatus. We speculated that the respiratory capacities of these subpopulations are differentially affected by pressure overload.
Hypertrophy as response to pressure-overload compensates for increased cardiac workload and energy demands. However, its presence is also an independent predictor of heart failure. We tested whether this association was related to defects in energy-substrate utilization.
Hypothesis: Pathological hypertrophy is associated with whole body insulin-resistance and the development of heart failure. Physiological hypertrophy is not. We compared substrate oxidation patterns and the effect of insulin in isolated working rat hearts with physiological or pathological hypertrophy.
Objectives: During the development of heart failure, a switch from fatty acid to glucose oxidation has been considered beneficial for contractile function. However, this mechanism requires intact mitochondrial function. We hypothesized that impairment in mitochondrial oxidative capacity limits beneficial effects of altered substrate preference in the setting of heart failure.
PGC-1alpha is a transcriptional coactivator that regulates gene expression of mitochondrial proteins and energy metabolic enzymes. In skeletal muscle, PGC-1alpha is induced by endurance training and thought to mediate the energy metabolic adaptation to exercise. We investigated the role of PGC-1alpha signaling in metabolic adaptation of the heart in response to exercise. Male Sprague Dawley rats were trained on treadmills for 10 weeks, resulting in increased left ventricular posterior wall diameter (1.84±0.13 vs. 2.35±0.15 mm, p<0.05), indicating physiological hypertrophy. Gene expression of PGC-1alpha and beta and their transcription factors (NRF1&2, ERRalpha, TFAm) was not different compared to controls. Similarly, expression of OXPHOS genes (Ndufa10, Uqcrc2, COXIV) was unchanged in treadmill-trained hearts. In accordance with gene expression, state 3 respiration of isolated mitochondria was not different from controls, using palmitoyl-carnitine, pyruvate, or glutamate as substrates (natomsO/min/mg protein: Control PC 121±30, Pyr 58±6, Glu 203±42). In contrast, mitochondrial state 3 respiration of the oxidative soleus muscle was tripled with all substrates (natomsO/min/mg protein: PC 150±18 vs. 453±125, Pyr 95±23 vs. 310±37, Glu 115±12 vs. 280±23, p<0.05). Since PGC-1alpha signaling may also regulate substrate oxidation, we investigated oxidation of fatty acids (FAO) and glucose (GO) in the isolated working rat heart using 0.4mM oleate and 5mM glucose. FAO was not different between groups (μmol/min/gdw: 0.99±0.07 vs. 0.92±1.10). While expression of PPARalpha was increased in treadmill trained rats (+49%, p<0.05), FAO genes were not differentially expressed (MCAD, LCAD, CPT1). GO was 40% lower in trained hearts (0.38±0.08 vs. 0.23±0.06 μmol/min/g dry, n.s.) and was accompanied by a trend towards increased PDK4 expression (+90%, p=0.059). The response to insulin was normal. Cardiac power in trained working hearts was also normal. We conclude that PGC-1 signaling may not mediate the cardiac hypertrophic response to exercise. In contrast to skeletal muscle, respiratory capacity is not increased in heart muscle after exercise. The metabolic phenotype of hypertrophied hearts in response to exercise is surprisingly normal.
PGC-1alpha is a transcriptional coactivator regulating gene expression of mitochondrial proteins and energy metabolic enzymes. In skeletal muscle, PGC-1alpha is induced by endurance training and thought to mediate the metabolic adaptation. We investigated the role of PGC-1alpha in the heart in response to exercise. Rats were treadmill trained (10weeks) inducing hypertrophy (LVPWD 1.84±0.13 vs. 2.35±0.15mm, p<0.05). Gene expression of PGC-1alpha/beta and transcription factors (NRF1&2, ERRalpha, TFAm) was not different from controls. Similarly, expression of respiratory chain genes was unchanged in trained hearts. In accordance with gene expression, state-3-respiration of isolated mitochondria was not different from controls independent of the substrate tested (natomsO/min/mg protein: palmitoyl-carnitine 121±30, pyruvate 58±6, glucose 203±42). In contrast, state 3 respiration of the oxidative soleus muscle was tripled with all substrates (natomsO/min/mg: palmitoyl-carnitine 150±18 vs. 453±125, pyruvate 95±23 vs. 310±37, glutamate 115±12 vs. 280±23, p<0.05). Since PGC-1alpha signaling may also regulate substrate oxidation, we investigated oxidation of fatty acids (FAO) and glucose (GO) in the isolated working rat heart. FAO and FAO gene expression was not different between groups (µmol/min/gdw: 0.99±0.07 vs. 0.92±1.10). GO was 40% lower in trained hearts (0.38±0.08 vs. 0.23±0.06µmol/min/gdry, ns) and was accompanied by substantially increased PDK4 expression (+90%, p=0.059). Cardiac power and the response to insulin in trained working hearts was normal.
Left ventricular hypertrophy is a risk factor for heart failure. However, it also is a compensatory response to pressure overload, accommodating for increased workload. We tested whether the changes in energy substrate metabolism may be predictive for the development of contractile dysfunction. Chronic pressure overload was induced in Sprague–Dawley rats by aortic arch constriction for 2, 6, 10, or 20 weeks. Contractile function in vivo was assessed by echocardiography and by invasive pressure measurement. Glucose and fatty acid oxidation as well as contractile function ex vivo were assessed in the isolated working heart, and respiratory capacity was measured in isolated cardiac mitochondria. Pressure overload caused progressive hypertrophy with normal ejection fraction (EF) at 2, 6, and 10 weeks, and hypertrophy with dilation and impaired EF at 20 weeks. The lung-to-body weight ratio, as marker for pulmonary congestion, was normal at 2 weeks (indicative of compensated hypertrophy) but significantly increased already after 6 and up to 20 weeks, suggesting the presence of heart failure with normal EF at 6 and 10 weeks and impaired EF at 20 weeks. Invasive pressure measurements showed evidence for contractile dysfunction already after 6 weeks and ex vivo cardiac power was reduced even at 2 weeks. Importantly, there was impairment in fatty acid oxidation beginning at 2 weeks, which was associated with a progressive decrease in glucose oxidation. In contrast, respiratory capacity of isolated mitochondria was normal until 10 weeks and decreased only in hearts with impaired EF. Pressure overload-induced impairment in fatty acid oxidation precedes the onset of congestive heart failure but mitochondrial respiratory capacity is maintained until the EF decreases in vivo. These temporal relations suggest a tight link between impaired substrate oxidation capacity in the development of heart failure and contractile dysfunction and may imply therapeutic and prognostic value.
