Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription

Abstract

Cellular hypertrophy is regulated by coordinated pro- and antigrowth machineries. Foxo transcription factors initiate an atrophy-related gene program to counter hypertrophic growth. This study was designed to evaluate the role of Akt, the forkhead transcription factor Foxo3a, and atrophy genes muscle-specific RING finger (MuRF)-1 and atrogin-1 in cardiac hypertrophy and contractile dysfunction associated with high-fat diet-induced obesity. Mice were fed a low- or high-fat diet for 6 mo along with a food-restricted high-fat weight control group. Echocardiography revealed decreased fractional shortening and increased end-systolic diameter and cardiac hypertrophy in high-fat obese but not in weight control mice. Cardiomyocytes from high-fat obese but not from weight control mice displayed contractile and intracellular Ca2+ defects including depressed maximal velocity of shortening/relengthening, prolonged duration of shortening/relengthening, and reduced intracellular Ca2+ rise and clearance. Caspase activities were greater in high-fat obese but not in weight control mouse hearts. Western blot analysis revealed enhanced basal Akt and Foxo3a phosphorylation and reduced insulin-stimulated phosphorylation of Akt and Foxo3a without changes in total protein expression of Akt and Foxo3a in high-fat obese hearts. RT-PCR and immunoblotting results displayed reduced levels of the atrogens atrogin-1 and MuRF-1, the upregulated hypertrophic markers GATA4 and ciliary neurotrophic factor receptor-alpha, as well as the unchanged calcineurin and proteasome ubiquitin in high-fat obese mouse hearts. Transfection of H9C2 myoblast cells with dominant-negative Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 h)-induced GATA4 upregulation without an additive effect. Dominant-negative Foxo3a-induced upregulation of pAkt and repression of phosphatase and tensin homologue were abrogated by palmitic acid. These results suggest a cardiac hypertrophic response in high-fat diet-associated obesity at least in part through inactivation of Foxo3a by the Akt pathway.

Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca 2+ -Handling Protein Profile in Obese Rats

“…In fact, in a previous study, some investigators found myocardial contractile dysfunction in rats fed with high-fat diet-induced obesity for 6 months. 20 The increase in total distance running and peak oxygen consumption shows the effectiveness of our exercise training paradigm. Interestingly, the increase in total distance running was proportionally greater than the increase in peak oxygen consumption in exercise-trained rats.…”

“…Previous studies show that obesity causes cardiac dysfunction and decrease in SERCA2 activity and phosphorylation of PLN. 5,19 More recently, Fang et al 20 elegantly demonstrated that cardiac dysfunction and impairment in intracellular Ca 2ϩ handling in mice are attributed to high-fat diet-induced obesity rather than high-fat diet intake without weight gain. The present study extends these findings showing that chronic high-fat and sucrose diet-induced obesity provokes a reduction in left ventricular systolic function and phospho-Thr 17 -PLN and phosphoSer 2808 -RyR protein expression levels.…”

Lowering Body Weight in Obese Mice With Diastolic Heart Failure Improves Cardiac Insulin Sensitivity and Function: Implications for the Obesity Paradox

“…We therefore examined what effect weight loss had on the hypertrophic signaling pathway in the hearts of obese heart failure mice. Inhibition of FOXO and the decrease in downstream atrogin-1 expression have been implicated in HF-dietinduced cardiac hypertrophy (59). On the other hand, activation of FOXO has been shown to promote cardiac (60) and skeletal muscle atrophy (61).…”

Insulin-like growth factor-1 restores dexamethasone-induced heart growth arrest in rats: the role of the ubiquitin pathway

“…Studies showing that the E3-ligases are critical for maintenance of heart mass further support the concept that the Ub pathway plays an important role in heart physiology. [10][11][12] The Ub pathway has also been implicated in various conditions affecting the heart such as diabetes, dilated cardiomyopathy, oxidative stress, and ischemia-reperfusion injury. 8,[13][14][15] Animal studies suggest that cardiac muscle is more resistant to the catabolic effects of glucocorticoids compared to skeletal muscle.…”