Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes

Abstract

The network for cardiac fuel metabolism contains intricate sets of interacting pathways that result in both ATP-producing and non-ATP-producing end points for each class of energy substrates. The most salient feature of the network is the metabolic flexibility demonstrated in response to various stimuli, including developmental changes and nutritional status. The heart is also capable of remodeling the metabolic pathways in chronic pathophysiological conditions, which results in modulations of myocardial energetics and contractile function. In a quest to understand the complexity of the cardiac metabolic network, pharmacological and genetic tools have been engaged to manipulate cardiac metabolism in a variety of research models. In concert, a host of therapeutic interventions have been tested clinically to target substrate preference, insulin sensitivity, and mitochondrial function. In addition, the contribution of cellular metabolism to growth, survival, and other signaling pathways through the production of metabolic intermediates has been increasingly noted. In this review, we provide an overview of the cardiac metabolic network and highlight alterations observed in cardiac pathologies as well as strategies used as metabolic therapies in heart failure. Lastly, the ability of metabolic derivatives to intersect growth and survival are also discussed.

Keywords: cardiac metabolism; cardiac pathology; metabolic signaling; metabolic therapy.

Figure 1. Overview of the Metabolic Network

The energy-yielding substrates (fatty acids, glucose, ketones, and amino acids), via specific catabolic pathways, converge on acetyl CoA production with subsequent entry into the tricarboxylic acid (TCA) cycle. The final step of energy transfer is accomplished through oxidative phosphorylation (OxPhos), supplying greater than 95% of ATP consumed by the heart. The boxes (in pink) above each metabolic pathway indicate the pathological and/or physiological condition in which the specific substrate becomes a predominant contributor to metabolism. TAG, triacylglycerol; DGAT, diacylglycerol acyltransferase; ATGL, adipose triglyceride lipase; mCPT1, muscle form of carnitine palmitoyl transferase; PDH, pyruvate dehydrogenase; TCA, tricarboxcylic acid; O_2, oxygen.

Figure 2. Accessory Pathways of Glucose Metabolism

Multiple accessary pathways of glucose metabolism result in the production of metabolites that do not directly contribute to energy supply but are of important biological function. Evidence has suggested that these pathways are altered in the hypertrophied, failing, ischemic, and/or diabetic heart as indicated. Glycolysis: G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose 1,6-biphosphate; G3P, glyceraldehyde 3-phosphate. Pentose Phosphate Pathway (PPP): G6PD, glucose 6-phosphate dehydrogenase; 6-PGL, 6-phosphoglucono-δ-lactone; NADPH, nicotinamide adenine dinucleotide phosphate; 6-PG, 6-phosphogluconate; Ribulose 5-P, ribulose 5-phosphate; X5P, xylulose 5-phosphate, R5P, ribose 5-phosphate. Polyol Pathway: AR, aldose reductase. Hexosamine Biosynthetic Pathway (HBP): GFAT, glutamine fructose 6-phosphate amidotransferase; Glucosamine 6-P, glucosamine 6-phosphate; UDPGlcNAc, uridine diphosphate-N-acetylglucosamine; OGT, O-linked β-N-acetylglucosamine transferase.

Figure 3. Metabolic Remodeling and the Development of Heart Failure

Pathological hypertrophy in response to mechanical overload, e.g. hypertension, valvular disease or post-MI, is accompanied by metabolic remodeling characterized by decreases in fatty acid oxidation (FAO) and increases in glycolysis. This fetal-like metabolic profile decreases the capacity for ATP synthesis, consistent with the “energy starvation” model. In contrast, the elevated supply of substrates in the heart of obese and/or diabetic individuals leads to an upregulation of FAO with a concomitant decrease in glucose oxidation (Glc ox). This lipid overload condition impairs cardiac efficiency. Regardless of the precipitating factor, the persistent metabolic derangements elicit commonalities of decreased oxidative metabolism, increased oxidative stress, insulin resistance, lipid accumulation, and energy deprivation, all contributing to the progression of heart failure.

Figure 4. Metabolic Modulation of Growth and Survival Pathways

Interactions of lipids (blue), amino acids (green), and glucose (red) metabolism with pathways of hypertrophy, autophagy, and apoptosis as represented in the literature from various cell culture and animal models. SFAs, saturated fatty acids; UFAs, unsaturated fatty acids; BCAAs, branched chain amino acids; G6P, glucose 6-phosphate; mTOR, Mammalian Target of Rapamycin.