Abstract
The role of canonical Wnt signaling in metabolic regulation and development of physiological cardiac hypertrophy remains largely unknown. To explore the function of β-catenin in the regulation of cardiac metabolism and physiological cardiac hypertrophy development, we used mice heterozygous for cardiac-specific β-catenin knockout that were subjected to a swimming training model. β-Catenin haploinsufficient mice subjected to endurance training displayed a decreased β-catenin transcriptional activity, attenuated cardiomyocytes hypertrophic growth, and enhanced activation of AMP-activated protein kinase (AMPK), phosphoinositide-3-kinase–Akt (Pi3K–Akt), and mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2 (MAPK/Erk1/2) signaling pathways compared to trained wild type mice. We further observed an increased level of proteins involved in glucose aerobic metabolism and β-oxidation along with perturbed activity of mitochondrial oxidative phosphorylation complexes (OXPHOS) in trained β-catenin haploinsufficient mice. Taken together, Wnt/β-catenin signaling appears to govern metabolic regulatory programs, sustaining metabolic plasticity in adult hearts during the adaptation to endurance training.
Highlights
Endurance training causes the development of physiological heart hypertrophy, known as athletic heart
Training led to a significant increase in heart weight (HW)/tibia length (TL) in WT/WT, but there was no difference in the HW/TL ratio between WT/CKO trained and sedentary controls (p = 0.37)
The key role of canonical Wnt signaling in maladaptive heart remodeling is well established, since the activation of β-catenin is necessary for pathological heart remodeling, which is associated with cardiomyocytes hypertrophy [9,10,11,12,13,14,15]
Summary
Endurance training causes the development of physiological heart hypertrophy, known as athletic heart. Pressure-induced pathological cardiac hypertrophy is orchestrated by calcineurin–nuclear factor of activated T cells pathway, Janus kinase–signal transducers, and activators of transcription pathway, Pi3K–Akt, MAPK/Erk1/2, canonical Wnt, and G-protein-coupled receptor signaling cascades [2,3], whereas physiological hypertrophy is accompanied by increased Pi3K–Akt and AMPK signaling activities [5]. Both physiological and pathological hypertrophy are characterized by increased cardiomyocytes size that is governed by common Pi3K–Akt and MAPK/Erk1/2 signaling pathways [6,7] which have crosstalks with β-catenin signaling [8]. It is tempting to suggest that β-catenin can be involved in the development of physiological hypertrophy
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