Metabolic Mechanisms of Exercise-Induced Cardiac Remodeling

Abstract

Exercise has a myriad of physiological benefits that derive in part from its ability to improve cardiometabolic health. The periodic metabolic stress imposed by regular exercise appears fundamental in driving cardiovascular tissue adaptation. However, different types, intensities, or durations of exercise elicit different levels of metabolic stress and may promote distinct types of tissue remodeling. In this review, we discuss how exercise affects cardiac structure and function and how exercise-induced changes in metabolism regulate cardiac adaptation. Current evidence suggests that exercise typically elicits an adaptive, beneficial form of cardiac remodeling that involves cardiomyocyte growth and proliferation; however, chronic levels of extreme exercise may increase the risk for pathological cardiac remodeling or sudden cardiac death. An emerging theme underpinning acute as well as chronic cardiac adaptations to exercise is metabolic periodicity, which appears important for regulating mitochondrial quality and function, for stimulating metabolism-mediated exercise gene programs and hypertrophic kinase activity, and for coordinating biosynthetic pathway activity. In addition, circulating metabolites liberated during exercise trigger physiological cardiac growth. Further understanding of how exercise-mediated changes in metabolism orchestrate cell signaling and gene expression could facilitate therapeutic strategies to maximize the benefits of exercise and improve cardiac health.

Keywords: cardiomyopathy; cell signaling; exercise; glucose; heart; hypertrophy; metabokine; mitochondria.

Figure 1

Exercise-mediated changes in cardiac function and in the tissue distribution of cardiac output. (A) Generalized schematic of cardiac responses to a moderate to intense, 1 h session of aerobic exercise. (B) Distribution of cardiac output at rest and with increasingly intense levels of exercise. Data are adapted from Plowman and Smith (38).

Figure 2

Exercise-induced cardiac growth. Aerobic and resistance exercise elicit different forms of physiological cardiac remodeling. Hypertrophic responses are primarily eccentric in nature for aerobic exercise and concentric in nature for resistance exercise. LA, left atrium; LV, left ventricle; LVWT, left ventricular wall thickness; RA, right atrium; RV, right ventricle.

Figure 3

Cardiac metabolism at rest and during exercise. The heart uses numerous substrates for energy provision, with the predominant sources for ATP production being fatty acids, glucose, and lactate. During exercise, lipolysis in adipose tissue and glycolysis in working skeletal muscle increase the circulating levels of fatty acids and lactate, respectively, which are used by the heart to fuel increased energy demands. ^*Other = ketone bodies, pyruvate, acetate, and branched chain amino acids.

Figure 4

Working model of the metabolic mechanisms of exercise-induced cardiac growth. (A) Periodic changes in glucose metabolism and mitochondrial activity (i.e., metabolic periodicity) occurring with regular exercise promote activation of gene programs responsible for cardiac growth, regulate mitochondrial quality control and function, activate prohypertrophic kinases, and coordinate biosynthetic pathways, all of which integrate to promote cardiac growth. (B) Exercise increases levels of circulating cardiac substrates and catecholamines, which orchestrate changes in cardiomyocyte metabolism. Decreases in the phosphorylation of phosphofructokinase 2 (PFK2) lower phosphofructokinase 1 (PFK1) activity, which decreases glucose catabolism, coordinates ancillary biosynthetic pathways, and increases the levels of upstream glycolytic intermediates (e.g., glucose 6-phosphate, G6P) as well as increases products in the pentose phosphate pathway (e.g., AICAR). Decreases in PFK activity and glucose catabolism appear sufficient to decrease expression of Cebpb and upregulate Cited4, which promote cardiac growth. In addition, elevated levels of G6P, AMP, and AICAR could activate the prohypertrophic signaling kinase mTOR and AMPK. Catecholamine-triggered signaling cascades promote mitochondrial fission and upregulate PGC1α, which acutely increase mitochondrial function and chronically elevate mitochondrial abundance and fatty acid oxidation (FAO) capacity. Last, circulating metabolites (e.g., palmitoleate) may also contribute to exercise-induced physiological cardiac growth.