Molecular Mechanisms Underlying Cardiac Adaptation to Exercise

Abstract

Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart, and lung. In the short term, the output of the heart increases to meet the demand of strenuous exercise. Long-term exercise instigates remodeling of the heart including growth and adaptive molecular and cellular re-programming. Signaling pathways such as the insulin-like growth factor 1/PI3K/Akt pathway mediate many of these responses. Exercise-induced, or physiologic, cardiac growth contrasts with growth elicited by pathological stimuli such as hypertension. Comparing the molecular and cellular underpinnings of physiologic and pathologic cardiac growth has unveiled phenotype-specific signaling pathways and transcriptional regulatory programs. Studies suggest that exercise pathways likely antagonize pathological pathways, and exercise training is often recommended for patients with chronic stable heart failure or following myocardial infarction. Herein, we summarize the current understanding of the structural and functional cardiac responses to exercise as well as signaling pathways and downstream effector molecules responsible for these adaptations.

Figure 1. Concentric compared to eccentric cardiac growth due to physiologic or pathologic stress

The normal heart will adapt to an increase in hemodynamic demand whether it is due to physiologic (e.g. exercise) or to pathologic (e.g. hypertension) stimuli. This hypertrophic growth, follows 2 typical patterns of growth determined by geometric relationship between ventricular internal diameter (LVD) and ventricular wall thickness, or relative wall thickness (RWT): (1) a concomitant increase in ventricular wall thickness and LVD (eccentric), usually driven by volume overload; (2) a disproportionate increase in wall thickness compared to LVD (concentric), driven by pressure overload. Typically, eccentric or concentric growth due exercise (Physiologic) is limited to a 12-15% increase in overall heart weight and does not progress to heart failure. In contrast, cardiac growth due to disease such as hypertension, myocardial infarction, or hypertrophic cardiomyopathy (Pathologic) usually exhibits a more robust hypertrophic response (concentric or eccentric) and often progress to a heart failure state. Pathologic eccentric growth may represent early transition to a dilated state; pathologic concentric growth results in profound thickening of the ventricular wall with a reduction in LVD.

Figure 2. Molecular and metabolic signatures distinguish pathologic and physiologic cardiac remodeling

Different external stimuli trigger distinct growth programs in the cardiomyocyte. In response to hypertension or pressure overload (Pathologic), the cardiomyocyte activates a growth program characterized by the induction of a fetal gene program including increased natriuretic peptide expression and changes in sarcomere isoform gene expression. This program eventually leads to a more global pathologic remodeling including left ventricular dilation and diminished cardiac function en route to the syndrome of heart failure. In contrast, exercise (Physiologic) elicits a growth program without induction of the fetal-gene program and an increase in energy metabolic capacity that matches the increase energy demands imposed by chronic exercise. This latter program maintains normal cardiac function. MHC, myosin heavy chain; ANF, atrial natriuretic factor; BNP, brain natriuretic peptide; FAO, fatty acid oxidation; PPARα, peroxisome proliferator activated receptor α; PGC-1, PPARγ coactivator-1α.

Figure 3

Cellular signaling pathways and transcriptional regulatory circuits mediating physiologic cardiac hypertrophic growth. Multiple growth factor pathways feed into the PI3K(p110α)-Akt signaling pathway including insulin growth factor 1 (IGF-1) and insulin to promote the physiologic hypertrophic response to exercise. These pathways directly antagonize pathologic growth growth. Exercise also enhances capacity for fuel oxidation and ATP production through peroxisome proliferator activated γ coactivator-1α (PGC-1α) regulated pathways that increase mitochondrial biogenesis and expression of genes involved in fatty acid β-oxidation. There is also evidence that cross-talk from growth factor signaling or eNOS to PGC-1α coordinates growth and metabolic pathways through unknown mechanisms (dotted line). Growth factors and signaling molecules that promote physiologic growth are shown in green; shown in red are those factors that antagonize physiologic growth. Transcription factors and coregulators are shown in blue. IRS-1, insulin receptor substrate 1; CREB, cAMP response element binding protein; eNOS, endothelial nitric oxide synthase; NRF, nuclear respiratory factor; ERR, estrogen-related receptor; PPAR, peroxisome proliferator activated receptor; C/EBPβ, CCAAT-enhancer binding protein β; CITED4, CBP/p300–interacting transactivator with ED-rich carboxy-terminal domain-4.