Impairment of the Transcriptional Responses to Oxidative Stress in the Heart of Aged C57BL/6 Mice

Edwards, Michael G.; Sarkar, Deepayan; Klopp, Roger G.; Morrow, Jason D.; Weindruch, Richard; Prolla, Tomas A.

doi:10.1196/annals.1297.017

Cited by 24 publications

(15 citation statements)

References 29 publications

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“…The increased levels of ROS produced by oxidative stress are known to induce expression of multiple genes, including PGC-1α and GADD45 (26,27). In parallel with the increased level of ROS in Sirt3 KD cells, there were significant increases in expression of these genes in the basal state, and these were further enhanced after H 2 O 2 treatment with no change in Sirt3 mRNA expression (Fig.…”

Section: Sirt3 Knockout Mice Exhibit Impaired Insulin Signaling and Imentioning

confidence: 84%

Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production

Jing

Emanuelli

Hirschey

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

416

331

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Sirt3 is a member of the sirtuin family of protein deacetylases that is localized in mitochondria and regulates mitochondrial function. Sirt3 expression in skeletal muscle is decreased in models of type 1 and type 2 diabetes and regulated by feeding, fasting, and caloric restriction. Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling. This effect is mimicked by knockdown of Sirt3 in cultured myoblasts, which exhibit reduced mitochondrial oxidation, increased reactive oxygen species, activation of JNK, increased serine and decreased tyrosine phosphorylation of IRS-1, and decreased insulin signaling. Thus, Sirt3 plays an important role in diabetes through regulation of mitochondrial oxidation, reactive oxygen species production, and insulin resistance in skeletal muscle.mitochondrial metabolism | protein acetylation I nsulin resistance in skeletal muscle is a major and early feature in the pathogenesis of type 2 diabetes (1, 2). This pathological condition has been shown to involve decreased activity of the insulin signaling network with reduced tyrosine phosphorylation of the insulin receptor and its substrates, decreased activation of phosphatidylinositol 3-kinase (PI 3-kinase), and decreased activation of Akt/PKB (protein kinase B), leading to reduced glucose uptake and other metabolic abnormalities (3-5). Another early feature of type 2 diabetes is altered mitochondrial function in muscle. Reduced expression of multiple nuclear-encoded genes involved in mitochondrial oxidative phosphorylation and alterations in mitochondrial morphology have been observed in skeletal muscle of both rodent models of diabetes and humans with type 2 diabetes (6-8). Impaired mitochondrial lipid oxidation and glycolytic capacity have also been observed in individuals with diabetes and obesity, whereas enhanced mitochondrial lipid oxidation capacity has been associated with improved insulin resistance (9, 10). This reduced expression and/or activity of mitochondrial proteins has been closely associated with altered skeletal muscle physiology and metabolism. Some, but not all, studies have found similar alterations in skeletal muscle of individuals with a family history positive for type 2 diabetes (8, 11). Reduced oxidative capacity and reduced ATP synthesis rates have also been shown in individuals with type 2 diabetes and in some nondiabetic individuals with a family history for diabetes (12).In addition to its role in substrate metabolism, the mitochondrion is the major production site of reactive oxygen species (ROS). When ROS level is excessive or there is impaired ROS clearance, the oxidative stress response can activate serine/ threonine kinases such as protein kinase C, S6 kinase, and Jun N-terminal kinase (JNK), which can phosphorylate the insulin receptor (IR) and/or insulin receptor substrate (IRS) proteins (13-15), leading to a decrease in their tyrosine phosphorylation, decreased activation of PI 3-kinase and A...

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Section: Sirt3 Knockout Mice Exhibit Impaired Insulin Signaling and Imentioning

confidence: 84%

Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production

Jing

Emanuelli

Hirschey

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

416

331

View full text Add to dashboard Cite

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“…Several studies have identified age-associated downregulation of genes involved in metabolism, mitochondrial function, protein synthesis, processing, transport and turnover [8, 27, 30, 34, 38, 65, 66], consistent with the loss of proteostasis and mitochondrial dysfunction identified as hallmarks of aging [1]. Intriquingly, genes associated with mitochondrial function are also implicated in longevity [55, 67, 68].…”

Section: What Types Of Genes Show Age-associated Changes In Expression?mentioning

confidence: 99%

Transcriptional Signatures of Aging

Stegeman

Weake

2017

Journal of Molecular Biology

129

100

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Genome-wide studies of aging have identified subsets of genes that show age-related changes in expression. Although the types of genes that are age-regulated vary among different tissues and organisms, some patterns emerge from these large data sets. First, aging is associated with a broad induction of stress response pathways, although the specific genes and pathways involved differ depending on cell type and species. In contrast, a wide variety of functional classes of genes are downregulated with age, often including tissue-specific genes. Whereas the upregulation of age-regulated genes is likely to be governed by stress-responsive transcription factors, questions remain as to why particular genes are susceptible to age-related transcriptional decline. Here, we discuss recent findings showing that splicing is misregulated with age. While defects in splicing could lead to changes in protein isoform levels, they could also impact gene expression through nonsense-mediated decay of intron-retained transcripts. The discovery that splicing is misregulated with age suggests that other aspects of gene expression, such as transcription elongation, termination and polyadenylation, must also be considered as potential mechanisms for age-related changes in transcript levels. Moreover, the considerable variation between genome-wide aging expression studies indicates that there is a critical need to analyze the transcriptional signatures of aging in single cell types rather than whole tissues. Since age-associated decreases in gene expression could contribute to a progressive decline in cellular function, understanding the mechanisms that determine the aging transcriptome provides a potential target to extend healthy cellular lifespan.

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“…As a result, aging increases wall stress that is not normalized by ventricular remodeling 36 . Furthermore, induction of cell protective mechanisms, such as expression of anti-oxidant and heat shock proteins, in response to pathologic insults is attenuated in aging hearts 33, 37, 38 . Optimal therapeutic interventions to alleviate the adverse effects of aging should prevent cell death and accumulation of senescent myocytes 22 .…”

Section: Manifestation Of Aging In the Heartmentioning

confidence: 99%

Aging and Autophagy in the Heart

Shirakabe

Ikeda

Sciarretta

et al. 2016

Circulation Research

372

273

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The aging population is increasing in developed countries. Since the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as “autophagy”) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by accumulation of misfolded proteins and dysfunctional organelles. On the other hand, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart. Increasing lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction, in various organisms. These results raise the exciting possibility that autophagy may play an important role in combating the adverse effects of aging in the heart. In this review, we discuss the role of autophagy in the heart during aging, how autophagy alleviates age-dependent changes in the heart, and how the level of autophagy in the aging heart can be restored.

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Impairment of the Transcriptional Responses to Oxidative Stress in the Heart of Aged C57BL/6 Mice

Cited by 24 publications

References 29 publications

Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production

Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production

Transcriptional Signatures of Aging

Aging and Autophagy in the Heart

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