Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating multiple targets.

Background: During cancer cachexia, cytokines released from tumour cells can alter body's metabolism, which can lead to onset of this disease process. Biological basis of cachexia is multifactorial; hence, it is important to identify and modulate multiple targets to curtail the process of cachexia. Previously, we reported that the nuclear sirtuin, SIRT6, blocks expression of myostatin, a negative regulator of muscle growth, through modulation of the NF-κB signalling.

The nuclear sirtuin SIRT6 protects the heart from developing aging-associated myocyte senescence and cardiac hypertrophy.

Sirtuins have been shown to regulate the aging process. We have previously demonstrated that Sirt6 blocks the pressure overload-induced cardiac hypertrophy in mice. Here, we show that Sirt6 can also mitigate aging-induced cardiomyocyte senescence and cardiac hypertrophy.

Is nuclear sirtuin SIRT6 a master regulator of immune function?

The ability to ward off pathogens with minimal damage to the host determines the immune system's robustness. Multiple factors, including pathogen processing, identification, secretion of mediator and effector molecules, and immune cell proliferation and differentiation into various subsets, constitute the success of mounting an effective immune response. Cellular metabolism controls all of these intricate processes.

The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity-mediated diabetic cardiomyopathy.

Sirtuins (Sirts) are implicated in regulating a myriad of biologic functions ranging from cell growth and metabolism to longevity. Here, we show that nuclear Sirt, Sirt6, and mitochondrial Sirt, Sirt3, regulate each other's activity and protect the heart from developing diabetic cardiomyopathy. We found that expression of both Sirt6 and Sirt3 was reduced in cardiomyocytes treated with palmitate and in hearts of mice fed with a high-fat, high-sucrose (HF-HS) diet to develop obesity and diabetes.

Cellular mechanisms promoting cachexia and how they are opposed by sirtuins .

Many chronic diseases are associated with unintentional loss of body weight, which is termed "cachexia". Cachexia is a complex multifactorial syndrome associated with the underlying primary disease, and characterized by loss of skeletal muscle with or without loss of fat tissue. Patients with cachexia face dire symptoms like dyspnea, fatigue, edema, exercise intolerance, and low responsiveness to medical therapy, which worsen quality of life.

The histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy.

Muscle wasting, also known as cachexia, is associated with many chronic diseases, which worsens prognosis of primary illness leading to enhanced mortality. Molecular basis of this metabolic syndrome is not yet completely understood. SIRT6 is a chromatin-bound member of the sirtuin family, implicated in regulating many cellular processes, ranging from metabolism, DNA repair to aging.

Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice.

Doxorubicin is the chemotherapeutic drug of choice for a wide variety of cancers, and cardiotoxicity is one of the major side effects of doxorubicin treatment. One of the main cellular targets of doxorubicin in the heart is mitochondria. Mitochondrial sirtuin, SIRT3 has been shown to protect against doxorubicin-induced cardiotoxicity.

SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage.

Myofibroblast differentiation is a key process in the pathogenesis of fibrotic diseases. Transforming growth factor-β (TGF-β) is a powerful inducer of myofibroblast differentiation and is implicated in pathogenesis of tissue fibrosis. This study was undertaken to determine the role of mitochondrial deacetylase SIRT3 in TGF-β-induced myofibroblast differentiation in vitro and lung fibrosis in vivo.

Role of Sirtuins in Regulating Pathophysiology of the Heart.

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.

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β.

Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is transforming growth factor β1 (TGF-β1)-mediated transformation of fibroblasts into myofibroblasts, cells capable of synthesizing extracellular matrix. Here, we show that SIRT3 controls transformation of fibroblasts into myofibroblasts via suppressing the profibrotic TGF-β1 signaling.

Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity.

Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II histone deacetylase (HDAC), HDAC4, and a histone acetyltransferase, p300/CREB-binding protein-associated factor, associate with cardiac sarcomeres and that a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres.

Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3.

Honokiol (HKL) is a natural biphenolic compound derived from the bark of magnolia trees with anti-inflammatory, anti-oxidative, anti-tumour and neuroprotective properties. Here we show that HKL blocks agonist-induced and pressure overload-mediated, cardiac hypertrophic responses, and ameliorates pre-existing cardiac hypertrophy, in mice. Our data suggest that the anti-hypertrophic effects of HKL depend on activation of the deacetylase Sirt3.

Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging.

Cardiac hypertrophy is a multifactorial disease characterized by multiple molecular alterations. One of these alterations is change in the activity of Akt, which plays a central role in regulating a variety of cellular processes ranging from cell survival to aging. Akt activation is mainly achieved by its binding to phosphatidylinositol (3,4,5)-triphosphate.

SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress.

Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. There is significant evidence suggesting a stringent association between morphology and bioenergetics of mitochondria. Morphological alterations in mitochondria are linked to several pathological disorders, including cardiovascular diseases.

Nampt secreted from cardiomyocytes promotes development of cardiac hypertrophy and adverse ventricular remodeling.

Nicotinamide phosphoribosyltransferase (Nampt) is an important coenzyme involved in cellular redox reactions. Inside the cell, Nampt (iNampt) functions as a rate-limiting enzyme in the NAD salvage pathway, and outside the cell (eNampt), it acts as a proinflammatory cytokine. High-circulating levels of Nampt are reported in different pathological conditions.

The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun.

Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling.

The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.

Signaling through the kinase Akt regulates many biological functions. Akt is activated during growth factor stimulation through a process that requires binding of Akt to phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), which promotes membrane localization and phosphorylation of Akt by the upstream kinase PDK1 (phosphoinositide-dependent protein kinase 1). We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding.

Acetylation of a conserved lysine residue in the ATP binding pocket of p38 augments its kinase activity during hypertrophy of cardiomyocytes.

Like phosphorylation, acetylation of lysine residues within a protein is considered a biologically relevant modification that controls the activity of target proteins. During stress of cells, massive protein acetylation takes place. Here, we show that p38 mitogen-activated protein kinase (MAPK), which controls many biological functions during stress, is reversibly acetylated by PCAF/p300 and HDAC3.

Emerging roles of SIRT1 deacetylase in regulating cardiomyocyte survival and hypertrophy.

Calorie restriction is considered to be the best environmental intervention providing health benefits to mammals. The underlying mechanism of this intervention seems to be controlled by a group of NAD-dependent deacetylases, collectively called sirtuins. In mammals, there are seven sirtuin analogs, SIRT1-SIRT7.

HDAC3-dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity.

Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II histone deacetylase (HDAC), HDAC4, and a histone acetyltransferase, PCAF, associate with cardiac sarcomeres, and a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study, we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres.

Mitochondrial SIRT3 and heart disease.

Sirtuins are emerging as key regulators of many cellular functions including metabolism, cell growth, apoptosis, and genetic control of ageing. In mammals there are seven sirtuin analogues, SIRT1 to SIRT7. Among them SIRT3 is unique because this is the only analogue whose increased expression has been found to be associated with extended lifespan of humans.

Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway.

Since the discovery of NAD-dependent deacetylases, sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress response of cells. Here we show that agonist-induced cardiac hypertrophy is associated with loss of intracellular levels of NAD, but not exercise-induced physiologic hypertrophy. Exogenous addition of NAD was capable of maintaining intracellular levels of NAD and blocking the agonist-induced cardiac hypertrophic response in vitro as well as in vivo.

SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1.

Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of PARP1, which is independent of DNA damage.