Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation

Zhong, Yuan; Tang, Kai; Nattel, Stanley; Zhai, Ming; Gong, Shuxi; Yu, Qing; Zeng, Yanxi; Guangxi, E; Maimaiiaili, Nuerbiyemu; Wang, Jun; Xu, Yawei; Peng, Wenhui; Li, Hailing

doi:10.1016/j.redox.2023.102606

Cited by 11 publications

(4 citation statements)

References 45 publications

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“…Finally, regarding Myl4, it is worth noting that previous studies have reported that loss-of-function models of Myl4 exhibit morphological and electrical remodeling, leading to the development of arrhythmias. 41,42 Therefore, SNPiP may play a protective role in cardiac functions by upregulating Myl4 to suppress these remodeling processes.…”

Section: Discussionmentioning

confidence: 99%

“…Since only limited information regarding NO and NOS levels in the hearts of EdnrB -/+ mice is available, further investigation is warranted to address this issue and provide a more comprehensive level of understanding. Finally, with regard to Myl4, it is worth noting that previous studies have reported that loss-of-function models of Myl4 exhibit morphological and electrical remodeling, leading to the development of arrhythmias [42,43]. Therefore, SNPiP may play a protective role in cardiac functions by upregulating Myl4 to suppress these remodeling processes.…”

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confidence: 96%

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Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-Nitroso-N-Pivaloyl-d-Penicillamine: Implications for Improved Diastolic Function and Cardiac Performance

Takenaka,

Hirasaki,

Bono

et al. 2024

Journal of Cardiovascular Pharmacology

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We previously reported a novel compound called S-nitroso-N-pivaloyl-D-penicillamine (SNPiP), which was screened from a group of nitric oxide (NO) donor compounds with a basic chemical structure of S-nitroso-N-acetylpenicillamine (SNAP), to activate the non-neuronal acetylcholine (NNA) system. SNPiP-treated mice exhibited improved cardiac output and enhanced diastolic function, without an increase in heart rate. The NNA-activating effects included increased resilience to ischemia, modulation of energy metabolism preference, and activation of angiogenesis. Here, we performed transcriptome analysis of SNPiP-treated mice ventricles to elucidate how SNPiP exerts beneficial effects on cardiac function. A time-course study (24 and 48 h after SNPiP administration) revealed that SNPiP initially induced Wnt and cGMP-protein kinase G (PKG) signaling pathways, along with upregulation of genes involved in cardiac muscle tissue development and oxytocin signaling pathway. We also observed enrichment of glycolysis-related genes in response to SNPiP treatment, resulting in a metabolic shift from oxidative phosphorylation to glycolysis, which was suggested by reduced cardiac glucose contents while maintaining ATP levels. Additionally, SNPiP significantly upregulated atrial natriuretic peptide (ANP) and sarcolipin (SLN), which play crucial roles in calcium handling and cardiac performance. These findings suggest that SNPiP may have therapeutic potential based on the pleiotropic mechanisms elucidated in this study.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-Nitroso-N-Pivaloyl-d-Penicillamine: Implications for Improved Diastolic Function and Cardiac Performance

Takenaka,

Hirasaki,

Bono

et al. 2024

Journal of Cardiovascular Pharmacology

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show abstract

“…A study by Peng et al [49] underscored a key role of MYL4 for atrial contractile, electrical and structural integrity via positive regulation of ATPase activity, enabling actin monomer binding. Variants in this gene were shown to cause progressive atrial fibrosis, leading to atrial cardiomyopathy and familial AF in humans and rats, while MYL4 loss-of-function was shown to block autophagy flux in atrial cardiomyocytes [50,51]. The other candidate modulator of RPL3L, SDHA, encodes a flavoprotein, a major catalytic subunit of the succinate dehydrogenase (SDH) enzyme, which is a key complex II protein of the mitochondrial respiratory chain that links two important pathways of ATP production in mitochondria, the Krebs cycle and oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Regulation and Function of Rpl3l in the Development of Early-Onset Dilated Cardiomyopathy and Congestive Heart Failure Using Systems Genetics Approach

Bajpai,

Gu,

Orgil

et al. 2023

Genes

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Background: Cardiomyopathies, diseases affecting the myocardium, are common causes of congestive heart failure (CHF) and sudden cardiac death. Recently, biallelic variants in ribosomal protein L3-like (RPL3L) have been reported to be associated with severe neonatal dilated cardiomyopathy (DCM) and CHF. This study employs a systems genetics approach to gain understanding of the regulatory mechanisms underlying the role of RPL3L in DCM. Methods: Genetic correlation, expression quantitative trait loci (eQTL) mapping, differential expression analysis and comparative functional analysis were performed using cardiac gene expression data from the patients and murine genetic reference populations (GRPs) of BXD mice (recombinant inbred strains from a cross of C57BL/6J and DBA/2J mice). Additionally, immune infiltration analysis was performed to understand the relationship between DCM, immune cells and RPL3L expression. Results: Systems genetics analysis identified high expression of Rpl3l mRNA, which ranged from 11.31 to 12.16 across murine GRPs of BXD mice, with an ~1.8-fold difference. Pathways such as “diabetic cardiomyopathy”, “focal adhesion”, “oxidative phosphorylation” and “DCM” were significantly associated with Rpl3l. eQTL mapping suggested Myl4 (Chr 11) and Sdha (Chr 13) as the upstream regulators of Rpl3l. The mRNA expression of Rpl3l, Myl4 and Sdha was significantly correlated with multiple echocardiography traits in BXD mice. Immune infiltration analysis revealed a significant association of RPL3L and SDHA with seven immune cells (CD4, CD8-naive T cell, CD8 T cell, macrophages, cytotoxic T cell, gamma delta T cell and exhausted T cell) that were also differentially infiltrated between heart samples obtained from DCM patients and normal individuals. Conclusions: RPL3L is highly expressed in the heart tissue of humans and mice. Expression of Rpl3l and its upstream regulators, Myl4 and Sdha, correlate with multiple cardiac function traits in murine GRPs of BXD mice, while RPL3L and SDHA correlate with immune cell infiltration in DCM patient hearts, suggesting important roles for RPL3L in DCM and CHF pathogenesis via immune inflammation, necessitating experimental validations of Myl4 and Sdha in Rpl3l regulation.

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“…Its expression product possesses Ca 2+ binding and motor activity, participating in the structural components of skeletal muscle, and is associated with muscle development and sarcomere contraction [12]. The most current research on the MYL4 gene focuses on cardiomyopathy [13,14]. However, with the continuous advancement of omics sciences, more evidence suggests the association of the MYL4 gene with muscle growth and development [15].…”

Section: Introductionmentioning

confidence: 99%

The Role of the MYL4 Gene in Porcine Muscle Development and Its Molecular Regulatory Mechanisms

Ye,

Wu,

Wang

et al. 2024

Animals

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Muscle growth stands as a pivotal economic trait within pig production, governed by a complex interplay of multiple genes, each playing a role in its quantitative manifestation. Understanding the intricate regulatory mechanisms of porcine muscle development is crucial for enhancing both pork yield and quality. This study used the GSE99749 dataset downloaded from the GEO database, conducting a detailed analysis of the RNA-seq results from the longissimus dorsi muscle (LD) of Tibetan pigs (TP), Wujin pigs (WJ) and large white pigs (LW) at 60 days of gestation, representing diverse body sizes and growth rates. Comparative analyses between TPvsWJ and TPvsLW, along with differential gene expression (DEG) analysis, functional enrichment analysis, and protein–protein interaction (PPI) network analysis, revealed 1048 and 1157 significantly differentially expressed genes (p < 0.001) in TPvsWJ and TPvsLW, respectively. With stricter screening criteria, 37 DEGs were found to overlap between the 2 groups. PPI analysis identified MYL5, MYL4, and ACTC1 as the three core genes. This article focuses on exploring the MYL4 gene. Molecular-level experimental validation, through overexpression and interference of the MYL4 gene combined with EDU staining experiments, demonstrated that overexpression of MYL4 significantly promoted the proliferation of porcine skeletal muscle satellite cells (PSMSC), while interference with MYL4 inhibited their proliferation. Furthermore, by examining the effects of overexpressing and interfering with the MYL4 gene on the muscle hypertrophy marker Fst gene and the muscle degradation marker FOXO3 gene, the pivotal role of the MYL4 gene in promoting muscle growth and preventing muscle degradation was further confirmed. These findings offer a new perspective on the molecular mechanisms behind porcine muscle growth and development, furnishing valuable data and insights for muscle biology research.

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Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation

Cited by 11 publications

References 45 publications

Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-Nitroso-N-Pivaloyl-d-Penicillamine: Implications for Improved Diastolic Function and Cardiac Performance

Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-Nitroso-N-Pivaloyl-d-Penicillamine: Implications for Improved Diastolic Function and Cardiac Performance

Exploring the Regulation and Function of Rpl3l in the Development of Early-Onset Dilated Cardiomyopathy and Congestive Heart Failure Using Systems Genetics Approach

The Role of the MYL4 Gene in Porcine Muscle Development and Its Molecular Regulatory Mechanisms

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