WNT/β‐catenin pathway is a key regulator of cardiac function and energetic metabolism

Abstract

The WNT/β‐catenin pathway is a master regulator of cardiac development and growth, and its activity is low in healthy adult hearts. However, even this low activity is essential for maintaining normal heart function. Acute activation of the WNT/β‐catenin signaling cascade is considered to be cardioprotective after infarction through the upregulation of prosurvival genes and reprogramming of metabolism. Chronically high WNT/β‐catenin pathway activity causes profibrotic and hypertrophic effects in the adult heart. New data suggest more complex functions of β‐catenin in metabolic maturation of the perinatal heart, establishing an adult pattern of glucose and fatty acid utilization. Additionally, low basal activity of the WNT/β‐catenin cascade maintains oxidative metabolism in the adult heart, and this pathway is reactivated by physiological or pathological stimuli to meet the higher energy needs of the heart. This review summarizes the current state of knowledge of the organization of canonical WNT signaling and its function in cardiogenesis, heart maturation, adult heart function, and remodeling. We also discuss the role of the WNT/β‐catenin pathway in cardiac glucose, lipid metabolism, and mitochondrial physiology.

The role of β-catenin in cardiac diseases

“…Nineteen Wnt proteins have been identified in mammals. Among them, Wnt1, Wnt3a, Wnt7a, Wnt7b, Wnt 8 and Wnt 10a act as ligands to activate the canonical Wnt/β-catenin pathway ( Balatskyi et al, 2023 ). Wnts require glycosylation and palmitoylation to acquire the ability to be secreted, and these factors act in both an autocrine and paracrine manner.…”

“…β-Catenin was confirmed to affect the development and function of the heart by participating in the metabolism of cardiomyocytes ( Balatskyi et al, 2020 ; Balatskyi et al, 2021 ). A recent review showed that β-catenin could affect perinatal cardiometabolic maturation by altering glucose and fatty acid utilization ( Balatskyi et al, 2023 ). β-catenin ablation caused mitochondrial insufficiency in perinatal cardiomyocytes, and hearts with heterozygous β-catenin ablation failed to increase mitochondrial numbers in response to exercise training ( Balatskyi et al, 2020 ; Balatskyi et al, 2021 ).…”

“…Additionally, the ablation of emerin, an inhibitor of β-catenin nuclear import, leads to heart dysfunction and aggravates cardiac remodeling following pressure overload ( Stubenvoll et al, 2015 ). During the developmental stage of the heart, β-catenin ablation could lead to metabolic failure and significantly inhibit glycolysis in perinatal cardiomyocytes ( Balatskyi et al, 2023 ). In the prenatal stage, oxygen partial pressure is relatively low, the heart is dependent on hypoxia-inducible factor 1α (HIF-1α) and rapamycin-driven metabolic patterns of mammalian/mechanical targets, and energy production occurs primarily through glycolysis ( Liang and Ward, 2006 ).…”

“…In the prenatal stage, oxygen partial pressure is relatively low, the heart is dependent on hypoxia-inducible factor 1α (HIF-1α) and rapamycin-driven metabolic patterns of mammalian/mechanical targets, and energy production occurs primarily through glycolysis ( Liang and Ward, 2006 ). Synergies of β-catenin with HIF-1α and other TFs are thought to be required for metabolic patterning of the developing heart, which promotes cardiomyocyte proliferation in dense myocardium ( Balatskyi et al, 2023 ). In the adult heart, β-catenin activation appears to result in a similar cardiac response to utilize more glucose ( Balatskyi et al, 2023 ).…”

“…Synergies of β-catenin with HIF-1α and other TFs are thought to be required for metabolic patterning of the developing heart, which promotes cardiomyocyte proliferation in dense myocardium ( Balatskyi et al, 2023 ). In the adult heart, β-catenin activation appears to result in a similar cardiac response to utilize more glucose ( Balatskyi et al, 2023 ). Moreover, the regulatory effect of β-catenin on cardiomyocyte proliferation may also be related to the Hippo pathway ( Heallen et al, 2011 ).…”