scholarly journals Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation

2021 ◽  
Vol 22 (17) ◽  
pp. 9509
Author(s):  
Hongyi Zhou ◽  
Huabo Su ◽  
Weiqin Chen
Keyword(s):  
Transcriptional Activation ◽  
Nuclear Export ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Myogenic Differentiation ◽  
The Body ◽  
Muscle Disease ◽  
Sirtuin 1 ◽  
Myoblast Differentiation ◽  
Class Iii

As the largest tissue in the body, skeletal muscle has multiple functions in movement and energy metabolism. Skeletal myogenesis is controlled by a transcriptional cascade including a set of muscle regulatory factors (MRFs) that includes Myogenic Differentiation 1 (MYOD1), Myocyte Enhancer Factor 2 (MEF2), and Myogenin (MYOG), which direct the fusion of myogenic myoblasts into multinucleated myotubes. Neddylation is a posttranslational modification that covalently conjugates ubiquitin-like NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to protein targets. Inhibition of neddylation impairs muscle differentiation; however, the underlying molecular mechanisms remain less explored. Here, we report that neddylation is temporally regulated during myoblast differentiation. Inhibition of neddylation through pharmacological blockade using MLN4924 (Pevonedistat) or genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1), a subunit of the E1 neddylation-activating enzyme, blocks terminal myoblast differentiation partially through repressing MYOG expression. Mechanistically, we found that neddylation deficiency enhances the mRNA and protein expressions of class IIa histone deacetylases 4 and 5 (HDAC4 and 5) and prevents the downregulation and nuclear export of class III HDAC (NAD-Dependent Protein Deacetylase Sirtuin-1, SIRT1), all of which have been shown to repress MYOD1-mediated MYOG transcriptional activation. Together, our findings for the first time identify the crucial role of neddylation in mediating class IIa and III HDAC co-repressors to control myogenic program and provide new insights into the mechanisms of muscle disease and regeneration.

scholarly journals Requirement for PINCH in Skeletal Myoblast Differentiation

2021 ◽  
Author(s):  
Siyi Xie ◽  
Chushan Fang ◽  
Yujie Gao ◽  
Jie Yan ◽  
Lina Luo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Molecular Mechanisms ◽  
Myogenic Differentiation ◽  
Critical Role ◽  
The Body ◽  
Myoblast Differentiation ◽  
Skeletal Myogenesis ◽  
Congenital Myopathies

Abstract Background: Skeletal muscle is composed of bundles of myofibers ensheathed by extracellular matrix networks. Malformation of skeletal muscle during embryonic development results in congenital myopathies. Disease mechanisms of congenital myopathies remain unclear. PINCH, an adaptor of focal adhesion complex, plays essential roles in multiple cellular processes and organogenesis. Elucidation of the molecular mechanisms underlying skeletal myogenesis will offer new insights into pathogenesis of myopathies.Methods: We generated muscle-specific PINCH knock-out mice to study the functional role of PINCH in skeletal myogenesis. Histologic and Transmission Electron Microscopy analysis demonstrated that Impaired myogenic differentiation and maturation in mice with PINCH1 being ablated in skeletal muscle progenitors, and Ablation of PINCH1 and PINCH2 resulted in reduced size of muscle fibers and impaired multinucleation; Cell culture and immunostaining showed that defects in myoblast fusion and cytoskeleton assembly in PINCH double mutant mice; Western blotting showed that defects in expression of cytoskeleton proteins and proteins involved in myogenesis in DMUT skeletal muscles.Results: Double ablation of PINCH1 and PINCH2 resulted in early postnatal lethality with reduced size of skeletal muscles and detachment of diaphragm muscles from the body wall. Myofibers of PINCH mutant myofibers failed to undergo multinucleation and exhibited disrupted sarcomere structures. The mutant myoblasts in culture were able to adhere to newly formed myotubes, but impeded in cell fusion and subsequent sarcomere genesis and cytoskeleton organization. Consistent with this, expression of integrin β1 and some cytoskeleton proteins, and phosphorylation of ERK and AKT were significantly reduced in PINCH mutants. Expression of MRF4, the most highly expressed myogenic factor at late stages of myogenesis, was abolished in PINCH mutants, that could contribute to observed phenotypes. In addition, mice with PINCH1 being ablated in myogenic progenitors exhibited only mild centronuclear myopathic changes, suggesting a compensatory role of PINCH2 in myogenic differentiation, indicating a critical role of PINCH proteins in myogenic differentiation.Conclusion: Our results demonstrated an essential role of PINCH in skeletal myogenic differentiation.

scholarly journals Sirtuin 1 (SIRT1) and steroid hormone receptor activity in cancer

2011 ◽  
Vol 213 (1) ◽  
pp. 37-48 ◽  
Author(s):  
R L Moore ◽  
Y Dai ◽  
D V Faller
Keyword(s):  
Cancer Progression ◽  
Hormone Receptor ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors ◽  
Sirtuin 1 ◽  
Steroid Hormone Receptor ◽  
Class Iii

Sirtuins, which are class III NAD-dependent histone deacetylases that regulate a number of physiological processes, play important roles in the regulation of metabolism, aging, oncogenesis, and cancer progression. Recently, a role for the sirtuins in the regulation of steroid hormone receptor signaling is emerging. In this mini-review, we will summarize current research into the regulation of estrogen, androgen, progesterone, mineralocorticoid, and glucocorticoid signaling by sirtuins in cancer. Sirtuins can regulate steroid hormone signaling through a variety of molecular mechanisms, including acting as co-regulatory transcription factors, deacetylating histones in the promoters of genes with nuclear receptor-binding sites, directly deacetylating steroid hormone nuclear receptors, and regulating pathways that modify steroid hormone receptors through phosphorylation. Furthermore, disruption of sirtuin activity may be an important step in the development of steroid hormone-refractory cancers.

Resveratrol

2017 ◽  
pp. 288-308 ◽  
Author(s):  
Catherine A. Powell ◽  
Jian Zhang ◽  
John D. Bowman ◽  
Mahua Choudhury
Keyword(s):  
Histone Deacetylases ◽  
Target Genes ◽  
Therapeutic Option ◽  
Genetic Regulation ◽  
The Body ◽  
Class Iii ◽  
Beneficial Effects ◽  
Epigenetic Regulator ◽  
Cardioprotective Effects ◽  
Genetic Makeup

Cardiovascular disease (CVD) is the leading cause of death in both men and women and has largely been attributed to genetic makeup and lifestyle factors. However, genetic regulation does not fully explain the pathophysiology. Recently, epigenetic regulation, the regulation of the genetic code by modifications that affect the transcription and translation of target genes, has been shown to be important. Silent information regulator-2 proteins or sirtuins are an epigenetic regulator family of class III histone deacetylases (HDACs), unique in their dependency on coenzyme NAD+, that are postulated to mediate the beneficial effects of calorie restriction, thus promoting longevity by reducing the incidence of chronic diseases such as cancer, diabetes, and CVD. Emerging evidence shows that SIRT1 is ubiquitously expressed throughout the body. Resveratrol, a plant polyphenol, has cardioprotective effects and its mechanism of action is attributed to regulation of SIRT1. Incoproation of resveratrol into the diet may be a powerful therapeutic option for the prevention and treatment of CVD.

scholarly journals The Role of Sirtuins in Kidney Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko
Keyword(s):  
Histone Deacetylases ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Class Iii ◽  
Cellular Functions ◽  
Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

Ratjadone C-Mediated Nuclear Accumulation of HDAC4: Implications on Runx2-Induced Osteoblast Differentiation of C3H10T1/2 Mesenchymal Stem Cells

2014 ◽  
Vol 69 (11-12) ◽  
pp. 471-478 ◽  
Author(s):  
Ping Mu ◽  
Vishwa Deepak ◽  
Liheng Kang ◽  
Qing Jiang ◽  
Rong Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Nuclear Export ◽  
Histone Deacetylases ◽  
Osteoblast Differentiation ◽  
Cellular Differentiation ◽  
Screening Tool ◽  
Nuclear Accumulation ◽  
Myoblast Differentiation ◽  
Nuclear Retention ◽  
Lysine Residues

Abstract Histone deacetylases (HDACs) are a group of enzymes that deacetylate ε-N-acetyl lysine residues of histone and non-histone proteins and play an important role in gene regulation. HDAC4, a class-IIa HDAC, has been reported to shuttle between nucleus and cytoplasm in response to various cellular stimuli. The nucleo-cytoplasmic shuttling of HDAC4 is critical, and an anomalous nuclear localization might affect the cellular differentiation program. While the subcellular localization of HDAC4 has been reported to be vital for myoblast differentiation and chondrocyte hypertrophy, nuclear accumulation of HDAC4 during Runx2-induced osteoblast differentiation of stem cells has not been characterized. Ratjadone C is a natural compound that inhibits the nuclear export of proteins. Here, we show that Runx2 is a more potent transcription factor than Osterix in inducing osteoblast differentiation. Under the influence of ratjadone C, HDAC4 is retained in the nucleus and co-localizes with Runx2. However, forced nuclear accumulation of HDAC4 by ratjadone C or overexpression of the nuclear resident form of HDAC4 does not inhibit osteoblast differentiation, suggesting that the Runx2- induced osteogenic program of C3H10T1/2 cells is not affected by HDAC4. Even though phosphorylation of HDAC4 affects its compartmentalization and the stemness of progenitor cells, we found that total HDAC4 and phosphorylated HDAC4 remain cytoplasmic under both osteogenic and nonosteogenic conditions. Collectively, this work demonstrates that, regardless of the nucleo-cytoplasmic presence of HDAC4, the Runx2-induced osteoblast differentiation program of C3H10T1/2 cells remains unaffected. Additionally, the ratjadone C-mediated nuclear retention assay can potentially be used as a screening tool to identify novel regulatory mechanisms of HDAC4 and its functional partners in various pathophysiological conditions.

scholarly journals Metabolic regulation of exercise-induced angiogenesis

2019 ◽  
Vol 1 (1) ◽  
pp. H1-H8 ◽  
Author(s):  
Tatiane Gorski ◽  
Katrien De Bock
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Metabolic Reprogramming ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Valuable Insight ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced

Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. In skeletal muscle, angiogenesis can occur via sprouting and splitting angiogenesis and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation of Vegf expression and increased muscle capillary density. While ECs are highly glycolytic and change their metabolism during sprouting angiogenesis in development and disease, a similar role for EC metabolism in exercise-induced angiogenesis in skeletal muscle remains to be elucidated. Nonetheless, recent studies have illustrated the importance of endothelial hydrogen sulfide and sirtuin 1 (SIRT1) activity for exercise-induced angiogenesis, suggesting that EC metabolic reprogramming may be fundamental in this process. We hypothesize that the exercise-induced angiogenic response can also be modulated by metabolic crosstalk between muscle and the endothelium. Defining the underlying molecular mechanisms responsible for skeletal muscle angiogenesis in response to exercise will yield valuable insight into metabolic regulation as well as the determinants of exercise performance.

scholarly journals Molecular Mechanisms, Therapeutic Targets and Pharmacological Interventions: An Update

2021 ◽  
Author(s):  
Mohit Kwatra ◽  
Sahabuddin Ahmed ◽  
Samir Ranjan Panda ◽  
Vegi Ganga Modi Naidu ◽  
Nitika Gupta
Keyword(s):  
Skeletal Muscle ◽  
Energy Expenditure ◽  
Muscle Mass ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Therapeutic Targets ◽  
The Body ◽  
Sirtuin 1 ◽  
Pharmacological Interventions ◽  
Ubiquitin Proteasome

Muscles are the enriched reservoir of proteins in the body. During any workout or exercise, the demand in the form of energy is essentially required by the muscle. Energy expenditure of skeletal muscle is more dependent on the type of demand. There is particular homeostasis within the body that avoid surplus energy expenditure and this prevents any muscle loss. Muscle atrophy is termed as the loss of skeletal muscle mass due to immobility, malnutrition, medications, aging, cancer cachexia, variety of injuries or diseases that impact the musculoskeletal or nervous system. Hence, atrophy within the skeletal muscle initiates further cause fatigue, pain, muscle weakness, and disability in human subjects. Therefore, starvation and reduced muscle mass further initiate numerous signaling pathways including inflammatory, antioxidant signaling, mitochondria bio-energetic failure, AMP-activated protein kinase (AMPK), Sirtuin 1(SIRT1), BDNF/TrkB/PKC, Autophagy, ubiquitin-proteasome systems, etc. Here, in this chapter, we will mention molecular mechanisms involved in therapeutic targets and available Pharmacological Interventions with the latest updates.

scholarly journals B cell Sirt1 deacetylates histone and non-histone proteins for epigenetic modulation of AID expression and the antibody response

2020 ◽  
Vol 6 (14) ◽  
pp. eaay2793 ◽  
Author(s):  
Huoqun Gan ◽  
Tian Shen ◽  
Daniel P. Chupp ◽  
Julia R. Taylor ◽  
Helia N. Sanchez ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Histone Deacetylases ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Dna Recombination ◽  
Sirtuin 1 ◽  
B Cell Differentiation ◽  
Class Iii ◽  
Nonhistone Proteins

Activation-induced cytidine deaminase (AID) mediates immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM), critical processes for maturation of the antibody response. Epigenetic factors, such as histone deacetylases (HDACs), would underpin B cell differentiation stage–specific AID expression. Here, we showed that NAD+-dependent class III HDAC sirtuin 1 (Sirt1) is highly expressed in resting B cells and down-regulated by stimuli inducing AID. B cell Sirt1 down-regulation, deprivation of NAD+ cofactor, or genetic Sirt1 deletion reduced deacetylation of Aicda promoter histones, Dnmt1, and nuclear factor–κB (NF-κB) p65 and increased AID expression. This promoted class-switched and hypermutated T-dependent and T-independent antibody responses or led to generation of autoantibodies. Genetic Sirt1 overexpression, Sirt1 boost by NAD+, or allosteric Sirt1 enhancement by SRT1720 repressed AID expression and CSR/SHM. By deacetylating histone and nonhistone proteins (Dnmt1 and NF-κB p65), Sirt1 transduces metabolic cues into epigenetic changes to play an important B cell–intrinsic role in modulating antibody and autoantibody responses.

scholarly journals Sirtuins: Molecular Traffic Lights in the Crossroad of Oxidative Stress, Chromatin Remodeling, and Transcription

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Ramkumar Rajendran ◽  
Richa Garva ◽  
Marija Krstic-Demonacos ◽  
Constantinos Demonacos
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Transcriptional Regulation ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Class Iii ◽  
Nonhistone Proteins ◽  
Traffic Lights ◽  
Major Mechanism

Transcription is regulated by acetylation/deacetylation reactions of histone and nonhistone proteins mediated by enzymes called KATs and HDACs, respectively. As a major mechanism of transcriptional regulation, protein acetylation is a key controller of physiological processes such as cell cycle, DNA damage response, metabolism, apoptosis, and autophagy. The deacetylase activity of class III histone deacetylases or sirtuins depends on the presence of NAD+(nicotinamide adenine dinucleotide), and therefore, their function is closely linked to cellular energy consumption. This activity of sirtuins connects the modulation of chromatin dynamics and transcriptional regulation under oxidative stress to cellular lifespan, glucose homeostasis, inflammation, and multiple aging-related diseases including cancer. Here we provide an overview of the recent developments in relation to the diverse biological activities associated with sirtuin enzymes and stress responsive transcription factors, DNA damage, and oxidative stress and relate the involvement of sirtuins in the regulation of these processes to oncogenesis. Since the majority of the molecular mechanisms implicated in these pathways have been described for Sirt1, this sirtuin family member is more extensively presented in this paper.

Identification of the crucial molecular events during the large-scale myoblast fusion in sheep

2014 ◽  
Vol 46 (12) ◽  
pp. 429-440 ◽  
Author(s):  
Caihong Wei ◽  
Li Li ◽  
Hongwei Su ◽  
Lingyang Xu ◽  
Jian Lu ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Muscle Development ◽  
Target Genes ◽  
Myogenic Differentiation ◽  
Myoblast Fusion ◽  
Myoblast Differentiation ◽  
Pcr Analysis ◽  
Fetal Sheep ◽  
Fetal Muscle

It is well known that in sheep most myofibers are formed before birth; however, the crucial myogenic stage and the cellular and molecular mechanisms underpinning phenotypic variation of fetal muscle development remain to be ascertained. We used histological, microarray, and quantitative real-time PCR (qPCR) methods to examine the developmental characteristics of fetal muscle at 70, 85, 100, 120, and 135 days of gestation in sheep. We show that day 100 is an important checkpoint for change in muscle transcriptome and histomorphology in fetal sheep and that the period of 85–100 days is the vital developmental stage for large-scale myoblast fusion. Furthermore, we identified the cis-regulatory motifs for E2F1 or MEF2A in a list of decreasingly or increasingly expressed genes between 85 and 100 days, respectively. Further analysis demonstrated that the mRNA and phosphorylated protein levels of E2F1 and MEF2A significantly declined with myogenic progression in vivo and in vitro. qRT-PCR analysis indicated that PI3K and FST, as targets of E2F1, may be involved in myoblast differentiation and fusion and that downregulation of MEF2A contributes to transition of myofiber types by differential regulation of the target genes involved at the stage of 85–100 days. We clarify for the first time the timing of myofiber proliferation and development during gestation in sheep, which would be beneficial to meat sheep production. Our findings present a repertoire of gene expression in muscle during large-scale myoblast fusion at transcriptome-wide level, which contributes to elucidate the regulatory network of myogenic differentiation.

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