Proteolysis regulates cardiomyocyte maturation and tissue integration

Fukuda, Ryūji; Gunawan, Felix; Beisaw, Arica; Jiménez-Amilburu, Vanesa; Maischein, Hans-Martin; Kostin, Sawa; Kawakami, Koichi; Stainier, Didier Y. R.

doi:10.1038/ncomms14495

Cited by 30 publications

(30 citation statements)

References 42 publications

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“…ASB2, a component of ECS-type (ElonginBC-Cullin-SOCS box) E3 ligase complex, has been shown to be essential for the cardiomyocyte maturation in zebrafish model ( Fukuda et al., 2017 ). In the heart of PRMT1-cKO mice, a large number of reads were detected following Asb2 exon 6 compared with control mice, indicating the existence of the extended form of exon 6 ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

PRMT1 Deficiency in Mouse Juvenile Heart Induces Dilated Cardiomyopathy and Reveals Cryptic Alternative Splicing Products

Murata

Hashimoto

et al. 2018

iScience

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SummaryProtein arginine methyltransferase 1 (PRMT1) catalyzes the asymmetric dimethylation of arginine residues in proteins and methylation of various RNA-binding proteins and is associated with alternative splicing in vitro. Although PRMT1 has essential in vivo roles in embryonic development, CNS development, and skeletal muscle regeneration, the functional importance of PRMT1 in the heart remains to be elucidated. Here, we report that juvenile cardiomyocyte-specific PRMT1-deficient mice develop severe dilated cardiomyopathy and exhibit aberrant cardiac alternative splicing. Furthermore, we identified previously undefined cardiac alternative splicing isoforms of four genes (Asb2, Fbxo40, Nrap, and Eif4a2) in PRMT1-cKO mice and revealed that eIF4A2 protein isoforms translated from alternatively spliced mRNA were differentially ubiquitinated and degraded by the ubiquitin-proteasome system. These findings highlight the essential roles of PRMT1 in cardiac homeostasis and alternative splicing regulation.

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Section: Resultsmentioning

confidence: 99%

PRMT1 Deficiency in Mouse Juvenile Heart Induces Dilated Cardiomyopathy and Reveals Cryptic Alternative Splicing Products

Murata

Hashimoto

et al. 2018

iScience

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“…MYBPH (the human ortholog of mybphb), on the other hand, is strongly expressed in muscle (Gilbert et al, 1999;Hayashi et al, 2016); together with sarcomeric myosin heavy chain, it can induce assembly of F-actin cables in nonmuscle cells (Welikson and Fischman, 2002). These two genes are also downregulated in asb2b mutant hearts, and asb2b, which encodes an E3 ubiquitin ligase, has been implicated in cardiomyocyte maturation (Fukuda et al, 2017) (Table S2). Moreover, asb2b −/− atrial cardiomyocytes, similar to wwtr1 −/− ventricular cardiomyocytes, exhibit aberrant N-cadherin localization.…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector Wwtr1 regulates cardiac wall maturation in zebrafish

et al. 2018

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Cardiac trabeculation is a highly regulated process that starts with the delamination of compact layer cardiomyocytes. The Hippo signaling pathway has been implicated in cardiac development but many questions remain. We have investigated the role of Wwtr1, a nuclear effector of the Hippo pathway, in zebrafish and find that its loss leads to reduced cardiac trabeculation. However, in mosaic animals, cardiomyocytes contribute more frequently than cardiomyocytes to the trabecular layer of wild-type hearts. To investigate this paradox, we examined the myocardial wall at early stages and found that compact layer cardiomyocytes in hearts exhibit disorganized cortical actin structure and abnormal cell-cell junctions. Accordingly, wild-type cardiomyocytes in mosaic mutant hearts contribute less frequently to the trabecular layer than when present in mosaic wild-type hearts, indicating that hearts are not able to support trabeculation. We also found that Nrg/Erbb2 signaling, which is required for trabeculation, could promote Wwtr1 nuclear export in cardiomyocytes. Altogether, these data suggest that Wwtr1 establishes the compact wall architecture necessary for trabeculation, and that Nrg/Erbb2 signaling negatively regulates its nuclear localization and therefore its activity.

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“…Rat neonatal (P1-P3) CMs were isolated as previously described (Fukuda et al, 2017), and CMs were further separated by density gradient centrifugation (Golden et al, 2012). Cells were plated onto 0.1% gelatin-coated (Sigma) plates and cultured in DMEM/F12 (Gibco) supplemented with 5% horse serum, L-glutamine, Na pyruvate, penicillin, and streptomycin at 37°C and 5% CO 2 .…”

Section: Cell Culturementioning

confidence: 99%

Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish

et al. 2020

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Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss-and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.

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Proteolysis regulates cardiomyocyte maturation and tissue integration

Cited by 30 publications

References 42 publications

PRMT1 Deficiency in Mouse Juvenile Heart Induces Dilated Cardiomyopathy and Reveals Cryptic Alternative Splicing Products

PRMT1 Deficiency in Mouse Juvenile Heart Induces Dilated Cardiomyopathy and Reveals Cryptic Alternative Splicing Products

The Hippo pathway effector Wwtr1 regulates cardiac wall maturation in zebrafish

Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish

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