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Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1α-Sirt3 signaling pathway. Shi Linying,Zhang Ting,Zhou Yong,Zeng Xianglong,Ran Li,Zhang Qianyong,Zhu Jundong,Mi Mantian Endocrine Insulin resistance in skeletal muscle is a key feature in the pathogenesis of type 2 diabetes (T2D) that often manifests early in its development. Pharmaceutical and dietary strategies have targeted insulin resistance to control T2D, and many natural products with excellent pharmacological properties are good candidates for the control or prevention of T2D. Dihydromyricetin (DHM) is a natural flavonol which provides a wide range of health benefits including anti-inflammatory and anti-tumor effects. However, little information is available regarding the effects of DHM on skeletal muscle insulin sensitivity as well as the underlying mechanisms. In the present study, we found that DHM activated insulin signaling and increased glucose uptake in skeletal muscle in vitro and in vivo. The expression of light chain 3, the degradation of sequestosome 1, and the formation of autophagosomes were also upregulated by DHM. DHM-induced insulin sensitivity improvement was significantly abolished in the presence of 3-methyladenine, bafilomycin A1, or Atg5 siRNA in C2C12 myotubes. Furthermore, DHM increased the levels of phosphorylated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), and Sirt3 in skeletal muscle in vitro and in vivo. Autophagy was inhibited in the presence of Sirt3 siRNA in C2C12 myotubes and in skeletal muscles from Sirt3-/- mice. Additionally, PGC-1α or AMPK siRNA transfection attenuated DHM-induced Sirt3 expression, thereby abrogating DHM-induced autophagy in C2C12 myotubes. In conclusion, DHM improved skeletal muscle insulin sensitivity by partially inducing autophagy via activation of the AMPK-PGC-1α-Sirt3 signaling pathway. 10.1007/s12020-015-0599-5
The sirtuins, oxidative stress and aging: an emerging link. Merksamer Philip I,Liu Yufei,He Wenjuan,Hirschey Matthew D,Chen Danica,Verdin Eric Aging Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice. Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROS-driven mitochondria-mediated hormetic response. 10.18632/aging.100544
Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins. Palmeira Carlos Marques,Teodoro João Soeiro,Amorim João Alves,Steegborn Clemens,Sinclair David A,Rolo Anabela Pinto Free radical biology & medicine The key role of mitochondria in oxidative metabolism and redox homeostasis explains the link between mitochondrial dysfunction and the development of metabolic disorders. Mitochondria's highly dynamic nature, based on alterations in biogenesis, mitophagy, fusion and fission, allows adjusting sequential redox reactions of the electron transport chain (ETC) and dissipation of the membrane potential by ATP synthase, to different environmental cues. With reactive oxygen species being an inevitable by-product of oxidative phosphorylation (OXPHOS), alterations on mitochondrial oxidative rate with a consequent excessive load of reactive oxygen species have been traditionally associated with pathological conditions. However, reactive oxygen species have also been suggested as promoters of mitohormesis, a process in which low, non-cytotoxic concentrations of reactive oxygen species promote mitochondrial homeostasis. Therefore, signaling systems involved in the regulation of mitochondrial homeostasis are attractive candidates for drug development for metabolic diseases triggered by mitochondrial dysfunction. Reversible phosphorylation downstream the cyclic AMP (cAMP) signaling cascade and deacetylation mediated by sirtuins are recognized as major mitochondrial regulators. 10.1016/j.freeradbiomed.2019.07.017
PGC-1α, Sirtuins and PARPs in Huntington's Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All. Neurochemical research In this review, we summarize the available published information on the neuroprotective effects of increasing nicotinamide adenine dinucleotide (NAD) levels in Huntington's disease models. We discuss the rationale of potential therapeutic benefit of administering nicotinamide riboside (NR), a safe and effective NAD precursor. We discuss the agonistic effect on the Sirtuin1-PGC-1α-PPAR pathway as well as Sirtuin 3, which converge in improving mitochondrial function, decreasing ROS production and ameliorating bioenergetics deficits. Also, we discuss the potential synergistic effect of increasing NAD+ combined with PARPs inhibitors, as a clinical therapeutic option not only in HD, but other neurodegenerative conditions. 10.1007/s11064-019-02809-1
The Role of Sirtuins in Antioxidant and Redox Signaling. Singh Chandra K,Chhabra Gagan,Ndiaye Mary Ann,Garcia-Peterson Liz Mariely,Mack Nicholas J,Ahmad Nihal Antioxidants & redox signaling SIGNIFICANCE:Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1-7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets. Recent studies show that sirtuins modulate the regulation of a variety of cellular processes associated with ARS. SIRT1, SIRT3, and SIRT5 protect the cell from ROS, and SIRT2, SIRT6, and SIRT7 modulate key oxidative stress genes and mechanisms. Interestingly, SIRT4 has been shown to induce ROS production and has antioxidative roles as well. CRITICAL ISSUES:A complete understanding of the roles of sirtuins in redox homeostasis of the cell is very important to understand the normal functioning as well as pathological manifestations. In this review, we have provided a critical discussion on the role of sirtuins in the regulation of ARS. We have also discussed mechanistic interactions among different sirtuins. Indeed, a complete understanding of sirtuin biology could be critical at multiple fronts. FUTURE DIRECTIONS:Sirtuins are emerging to be important in normal mammalian physiology and in a variety of oxidative stress-mediated pathological situations. Studies are needed to dissect the mechanisms of sirtuins in maintaining redox homeostasis. Efforts are also required to assess the targetability of sirtuins in the management of redox-regulated diseases. Antioxid. Redox Signal. 28, 643-661. 10.1089/ars.2017.7290
Role of NAD and mitochondrial sirtuins in cardiac and renal diseases. Hershberger Kathleen A,Martin Angelical S,Hirschey Matthew D Nature reviews. Nephrology The coenzyme nicotinamide adenine dinucleotide (NAD) has key roles in the regulation of redox status and energy metabolism. NAD depletion is emerging as a major contributor to the pathogenesis of cardiac and renal diseases and NAD repletion strategies have shown therapeutic potential as a means to restore healthy metabolism and physiological function. The pleotropic roles of NAD enable several possible avenues by which repletion of this coenzyme could have therapeutic efficacy. In particular, NAD functions as a co-substrate in deacylation reactions carried out by the sirtuin family of enzymes. These NAD-dependent deacylases control several aspects of metabolism and a wealth of data suggests that boosting sirtuin activity via NAD supplementation might be a promising therapy for cardiac and renal pathologies. This Review summarizes the role of NAD metabolism in the heart and kidney, and highlights the mitochondrial sirtuins as mediators of some of the beneficial effects of NAD-boosting therapies in preclinical animal models. We surmise that modulating the NAD-sirtuin axis is a clinically relevant approach to develop new therapies for cardiac and renal diseases. 10.1038/nrneph.2017.5
Role of Sirtuins in Regulating Pathophysiology of the Heart. Bindu Samik,Pillai Vinodkumar B,Gupta Mahesh P Trends in endocrinology and metabolism: TEM Cardiovascular diseases (CVDs) are expanding at an alarming rate and people's propensity to develop them increases with age. Growing evidence indicates that sirtuins play a pivotal role in regulating a multitude of age-related diseases. Sirtuins are versatile molecules conserved from archaea to mammals. They are regulated by various metabolic and environmental stimuli. Seven sirtuin homologs (SIRT1-7) are present in mammals, with diverse cellular locations. Recent studies have delineated roles of sirtuins in regulating cardiac pathophysiological conditions under various stressors. SIRT1 is the most extensively studied sirtuin, while the role of other sirtuins in maintaining cardiac growth and function is still emerging. In this review we discuss the present understanding of the role of sirtuins in regulating pathophysiological conditions of the heart. 10.1016/j.tem.2016.04.015
SIRT1 and other sirtuins in metabolism. Chang Hung-Chun,Guarente Leonard Trends in endocrinology and metabolism: TEM Sirtuins such as SIRT1 are conserved protein NAD(+)-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging. 10.1016/j.tem.2013.12.001
Emerging beneficial roles of sirtuins in heart failure. Tanno Masaya,Kuno Atsushi,Horio Yoshiyuki,Miura Tetsuji Basic research in cardiology Sirtuins are a highly conserved family of histone/protein deacetylases whose activity can prolong the lifespan of model organisms such as yeast, worms and flies. In mammalian cells, seven sirtuins (SIRT1-7) modulate distinct metabolic and stress-response pathways, SIRT1 and SIRT3 having been most extensively investigated in the cardiovascular system. SIRT1 and SIRT3 are mainly located in the nuclei and mitochondria, respectively. They participate in biological functions related to development of heart failure, including regulation of energy production, oxidative stress, intracellular signaling, angiogenesis, autophagy and cell death/survival. Emerging evidence indicates that the two sirtuins play protective roles in failing hearts. Here, we summarize current knowledge of sirtuin functions in the heart and discuss its translation into therapy for heart failure. 10.1007/s00395-012-0273-5
Recent progress in the biology and physiology of sirtuins. Finkel Toren,Deng Chu-Xia,Mostoslavsky Raul Nature The sirtuins are a highly conserved family of NAD(+)-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live. 10.1038/nature08197
Sirtuin 6: A potential therapeutic target for cardiovascular diseases. Pharmacological research Cardiovascular diseases (CVDs) are serious diseases endangering human health due to high morbidity and mortality worldwide, and numerous signal molecules are involved in this pathological process. As a member of the Sirtuin family NAD -dependent deacetylases, indeed, Sirtuin 6 (SIRT6) plays an important role in regulating biological homeostasis, longevity, and various diseases. More importantly, SIRT6 performs as an indispensable role in glucose and lipid metabolism, inflammation and genomic stability for the occurrence and development of various CVDs. Recent advances: among sirtuins, SIRT6 was frequently unveiled thanks for its protective roles against heart failure, cardiovascular remodeling and atherosclerosis, and identified as an essential intervention target of CVDs, bringing SIRT6 into the focus of clinical interest. Herein, we provide an overview of the current molecular mechanism through which SIRT6 regulates CVDs, and we highlight a potential therapeutic target for CVDs. 10.1016/j.phrs.2020.105214
The role of SIRT3 in mitochondrial homeostasis and cardiac adaptation to hypertrophy and aging. Sack Michael N Journal of molecular and cellular cardiology Although acetyl-modification of protein lysine residues has been recognized for many decades, the appreciation that this post-translational modification is highly prevalent in mitochondria and plays a pivotal regulatory role in mitochondrial function has only become apparent since 2006. The classical biological stressors that modulate mitochondrial protein acetylation include alterations in caloric levels and redox signaling and the major enzyme orchestrating deacetylation is the mitochondrial enriched sirtuin SIRT3. Overall the action of SIRT3 modulates mitochondrial homeostasis and SIRT3 target proteins include mediators of energy metabolism and mitochondrial redox stress adaptive program proteins. Given these effects, it is not surprising that the role of SIRT3 has begun to be implicated in cardiac biology. This review gives a brief overview of sirtuin biology and then focuses on the role of the SIRT3 regulatory program in the control of cardiac hypertrophy and aging. This article is part of a Special Section entitled "Post-translational Modification." 10.1016/j.yjmcc.2011.11.004
Sirtuin 3, Endothelial Metabolic Reprogramming, and Heart Failure With Preserved Ejection Fraction. Zeng Heng,Chen Jian-Xiong Journal of cardiovascular pharmacology The incidences of heart failure with preserved ejection fraction (HFpEF) are increased in aged populations as well as diabetes and hypertension. Coronary microvascular dysfunction has contributed to the development of HFpEF. Endothelial cells (ECs) depend on glycolysis rather than oxidative phosphorylation for generating adenosine triphosphate to maintain vascular homeostasis. Glycolytic metabolism has a critical role in the process of angiogenesis, because ECs rely on the energy produced predominantly from glycolysis for migration and proliferation. Sirtuin 3 (SIRT3) is found predominantly in mitochondria and its expression declines progressively with aging, diabetes, obesity, and hypertension. Emerging evidence indicates that endothelial SIRT3 regulates a metabolic switch between glycolysis and mitochondrial respiration. SIRT3 deficiency in EC resulted in a significant decrease in glycolysis, whereas, it exhibited higher mitochondrial respiration and more prominent production of reactive oxygen species. SIRT3 deficiency also displayed striking increases in acetylation of p53, EC apoptosis, and senescence. Impairment of SIRT3-mediated EC metabolism may lead to a disruption of EC/pericyte/cardiomyocyte communications and coronary microvascular rarefaction, which promotes cardiomyocyte hypoxia, Titin-based cardiomyocyte stiffness, and myocardial fibrosis, thus leading to a diastolic dysfunction and HFpEF. This review summarizes current knowledge of SIRT3 in EC metabolic reprograming, EC/pericyte interactions, coronary microvascular dysfunction, and HFpEF. 10.1097/FJC.0000000000000719
Mitochondrial Sirtuins and Doxorubicin-induced Cardiotoxicity. He Ling,Liu Fuxiang,Li Juxiang Cardiovascular toxicology Doxorubicin (DOX) is the most effective and extensively used treatment for many tumors. However, its clinical use is hampered by its cardiotoxicity. DOX-induced mitochondrial dysfunction, which causes reactive oxygen species (ROS) generation, cardiomyocyte death, bioenergetic failure, and decreased cardiac function, is a very important mechanism of cardiotoxicity. These cellular processes are all linked by mitochondrial sirtuins (SIRT3-SIRT4). Mitochondrial sirtuins preserve mitochondrial function by increasing mitochondrial metabolism, inhibiting ROS generation by activating the antioxidant enzyme manganese-dependent superoxide dismutase (MnSOD), decreasing apoptosis by activating the forkhead homeobox type O (FOXO) and P53 pathways, and increasing autophagy through AMP-activated protein kinase (AMPK)/mTOR signaling. Thus, sirtuins function at the control point of many mechanisms involved in DOX-induced cardiotoxicity. In this review, we focus on the role of mitochondrial sirtuins in mitochondrial biology and DOX-induced cardiotoxicity. A further aim is to highlight other mitochondrial processes, such as autophagy (mitophagy) and mitochondrial quality control (MQC), for which the effect of mitochondrial sirtuins on cardiotoxicity is unknown. 10.1007/s12012-020-09626-x