Cardiac-specific β-catenin deletion dysregulates energetic metabolism and mitochondrial function in perinatal cardiomyocytes

Balatskyi, V. V.; Vaskivskyi, Vasyl; Myronova, Anna; Avramets, Diana; Nahia, Karim Abu; Macewicz, L. L.; Рубан, Т. А.; Kucherenko, Dar'ya Yu.; Солдаткін, О. О.; Lushnikova, Iryna; Skibo, G. G.; Winata, Cecilia Lanny; Dobrzyń, Paweł; Piven, O. O.

doi:10.1016/j.mito.2021.07.005

Cited by 13 publications

(27 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…80 βcatenin ablation in cardiomyocytes at these developmental stages with αMHC-Cre leads to late embryonic and perinatal lethality because of a hypocellular myocardium. 33,147,148 Emerin is a negative regulator of βcatenin that limits βcatenin translocation to the nucleus. Emerin ablation leads to βcatenin hyperactivation, stimulates cardiomyocyte proliferation, impairs their terminal differentiation, and leads to a hypercellular myocardium.…”

Section: Canonical Wnt Pathway In Cardiogenesismentioning

confidence: 99%

“…The canonical WNT pathway is required for metabolic maturation of the perinatal heart, and low βcatenin transcriptional activity maintains metabolic homeostasis in the adult heart. 28,33 The present review provides an overview of organization of the WNT/β-catenin signaling pathway in cardiomyocytes and its role in cardiogenesis and adult heart remodeling. We also discuss the function of βcatenin signaling transduction in the regulation of glucose and lipid metabolism and maintenance of mitochondrion wellbeing.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2023

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Canonical Wnt Pathway In Cardiogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…26,[41][42][43] These pathways correlate closely to mitochondrial dysfunction in cardiovascular diseases. [44][45][46][47] Thus, a comprehensive understanding of the upstream mechanisms by which emerin regulate mitochondrial function would be a future direction of research favourable for investigating therapeutic strategies and genetic manipulations aimed to treat cardiac emerinopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that emerin regulates multiple signal pathways such as MAPK/ERK, MKL1‐SRF, wnt/β‐catenin, notch signalling, which may underlie cardiac defects observed in EDMD1 26,41–43 . These pathways correlate closely to mitochondrial dysfunction in cardiovascular diseases 44–47 . Thus, a comprehensive understanding of the upstream mechanisms by which emerin regulate mitochondrial function would be a future direction of research favourable for investigating therapeutic strategies and genetic manipulations aimed to treat cardiac emerinopathy.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in human EMD gene and mitochondrial dysfunction in emerin knockdown cardiomyocytes

Zhu

Lin

et al. 2022

J Cellular Molecular Medi

View full text Add to dashboard Cite

Emerin is an inner nuclear envelope protein encoded by the EMD gene, mutations in which cause Emery–Dreifuss muscular dystrophy type 1 (EDMD1). Cardiac involvement has become a major threat to patients with EDMD1; however, the cardiovascular phenotype spectrums of emerinopathy and the mechanisms by which emerin regulates cardiac pathophysiology remain unclear. Here, we identified a novel nonsense mutation (c.C57G, p.Y19X) in the EMD gene in a Han Chinese family through high‐throughput sequencing. Two family members were found to have EDMD1 with muscle weakness and cardiac arrhythmia. Mechanistically, we first discovered that knockdown of emerin in HL‐1 or H9C2 cardiomyocytes lead to impaired mitochondrial oxidative phosphorylation capacity with downregulation of electron transport chain complex I and IV and upregulation of complex III and V. Moreover, loss of emerin in HL‐1 cells resulted in collapsed mitochondrial membrane potential, altered mitochondrial networks and downregulated multiple factors in RNA and protein level, such as PGC1α, DRP1, MFF, MFN2, which are involved in regulation of mitochondrial biogenesis, fission and fusion. Our findings suggest that targeting mitochondrial bioenergetics might be an effective strategy against cardiac disorders caused by EMD mutations.

show abstract

“… 91 The reasons for discrepancies between these studies remain unclear; however, it is interesting that both studies found an interaction between Pkm2 and β-catenin in regulating cardiomyocyte cell cycle entry, 90 , 91 especially in light of the importance of β-catenin to energy metabolism in cardiomyocytes. 92 The interaction between Pkm2 and β-catenin is also required for recruitment of both proteins to the promoter of the cyclin D1 gene, 93 suggesting non-metabolic roles for Pkm2 in activation of the cell cycle as well. Of interest, Pkm2 also functions as a transcriptional co-activator by interacting directly with Hif1α, 94 highlighting feedback loops between metabolism and the transcriptional machinery.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Determinants of Cardiomyocyte Proliferation

2022

View full text Add to dashboard Cite

The adult mammalian heart is recalcitrant to regeneration after injury, in part due to the postmitotic nature of cardiomyocytes. Accumulating evidence suggests that cardiomyocyte proliferation in fetal or neonatal mammals and in regenerative non-mammalian models depends on a conducive metabolic state. Results from numerous studies in adult hearts indicate that conditions of relatively low fatty acid oxidation, low reactive oxygen species generation, and high glycolysis are required for induction of cardiomyocyte proliferation. Glycolysis appears particularly important because it provides branchpoint metabolites for several biosynthetic pathways that are essential for synthesis of nucleotides and nucleotide sugars, amino acids, and glycerophospholipids, all of which are required for daughter cell formation. In addition, the proliferative cardiomyocyte phenotype is supported in part by relatively low oxygen tensions and through the actions of critical transcription factors, coactivators, and signaling pathways that promote a more glycolytic and proliferative cardiomyocyte phenotype, such as hypoxia inducible factor 1α (Hif1α), Yes-associated protein (Yap), and ErbB2. Interventions that inhibit glycolysis or its integrated biosynthetic pathways almost universally impair cardiomyocyte proliferative capacity. Furthermore, metabolic enzymes that augment biosynthetic capacity such as phosphoenolpyruvate carboxykinase 2 and pyruvate kinase M2 appear to be amplifiers of cardiomyocyte proliferation. Collectively, these studies suggest that acquisition of a glycolytic and biosynthetic metabolic phenotype is a sine qua non of cardiomyocyte proliferation. Further knowledge of the regulatory mechanisms that control substrate partitioning to coordinate biosynthesis with energy provision could be leveraged to prompt or augment cardiomyocyte division and to promote cardiac repair.

show abstract

Cardiac-specific β-catenin deletion dysregulates energetic metabolism and mitochondrial function in perinatal cardiomyocytes

Cited by 13 publications

References 58 publications

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

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

A novel mutation in human EMD gene and mitochondrial dysfunction in emerin knockdown cardiomyocytes

Metabolic Determinants of Cardiomyocyte Proliferation

Contact Info

Product

Resources

About