Downregulation of Sirt1 as aging change in advanced heart failure

Lu, Tse Min; Tsai, Catherine Jia-Yun; Chen, Yen‐Chung; Huang, Cecilia; Hsu, Hung Lung; Weng, Chi Feng; Shih, Chun Che; Hsu, Chiao Po

doi:10.1186/1423-0127-21-57

Cited by 95 publications

(68 citation statements)

References 31 publications

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“…Sirt1 is reduced in aging and muscle wasting [28,42]. Although the mechanism for the loss of Sirt1 in aging is not known, we speculate that high levels of oxidative stress contribute to this loss in Sirt1.…”

Section: Resultsmentioning

confidence: 99%

Dietary resveratrol confers apoptotic resistance to oxidative stress in myoblasts

Haramizu

Asano

Butler

et al. 2017

The Journal of Nutritional Biochemistry

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High levels of reactive oxygen species (ROS) contributes to muscle cell death in aging and disuse. We have previously found that resveratrol can reduce oxidative stress in response to aging and hindlimb unloading in rodents in vivo, but it was not known if resveratrol would protect muscle stem cells during repair or regeneration when oxidative stress is high. To test the protective role of resveratrol on muscle stem cells directly, we treated the C2C12 mouse myoblast cell line with moderate (100 μM) or very high (1 mM) levels of H2O2; in the presence or absence of resveratrol. The p21 promoter activity declined in myoblasts in response to high ROS and this was accompanied a greater nuclear to cytoplasmic translocation of p21 in a dose dependent matter in myoblasts as compared to myotubes. Apoptosis, as indicated by TdT-mediated dUTP nick-end (TUNEL) labeling was greater in C2C12 myoblasts as compared to myotubes (P< 0.05) after treatment with H2O2. Caspase-9, -8, and -3 activities were elevated significantly (P< 0.05) in myoblasts treated with H2O2. Myoblasts were more susceptible to ROS-induced oxidative stress than myotubes. We treated C2C12 myoblasts with 50 μM of resveratrol for periods up to 48 h to determine if myoblasts could be rescued from high ROS-induced apoptosis by resveratrol. Resveratrol reduced the apoptotic index, and significantly reduced the ROS-induced caspase-9, -8, and -3 activity in myoblasts. Furthermore, Bcl-2 and the Bax/Bcl-2 ratio were partially rescued in myoblasts by resveratrol treatment. Similarly, muscle stem cells isolated from mouse skeletal muscles showed reduced Sirt1 protein abundance with H2O2 treatment but this could be reversed by resveratrol. Reduced apoptotic susceptibility in myoblasts as compared to myotubes to ROS is regulated at least in part, by enhanced p21 promoter activity and nuclear p21 location in myotubes. Resveratrol confers further protection against ROS by improving Sirt1 levels and increasing antioxidant production, which reduces mitochondrial associated apoptotic signaling, and cell death in myoblasts.

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Section: Resultsmentioning

confidence: 99%

Dietary resveratrol confers apoptotic resistance to oxidative stress in myoblasts

Haramizu

Asano

Butler

et al. 2017

The Journal of Nutritional Biochemistry

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“…In spontaneously hypertensive rats, compensatory cardiac hypertrophy was accompanied by a decrease in SIRT-1 expression (Tang, et al, 2014). Similarly, SIRT-1 expression was reduced in patients with both compensated and decompensated HF (Akkafa, et al, 2015) and in patients with advanced HF (Lu, et al, 2014). In both of these studies, SIRT-1 downregulation was associated with an increase in oxidative stress and pro-apoptotic signaling.…”

Section: Fatty Acid Metabolismmentioning

confidence: 87%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants.Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed.

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“…In the murine heart, ischemia results in decreased levels of SIRT1, and this decrease is accentuated with aging (Jian et al , 2011a; Lu et al , 2014; Tong et al , 2013). Furthermore, overexpression of SIRT1 in mice results in decreased ischemia reperfusion induced myocardial infarction while decreased expression potentiates the degree of infarction (Hsu et al , 2010).…”

Section: Pharmacologic Therapiesmentioning

confidence: 99%

Mitochondrial function in hypoxic ischemic injury and influence of aging

Ham

Raju

2017

Progress in Neurobiology

282

205

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Mitochondria are a major target in hypoxic/ischemic injury. Mitochondrial impairment increases with age leading to dysregulation of molecular pathways linked to mitochondria. The perturbation of mitochondrial homeostasis and cellular energetics worsens outcome following hypoxic-ischemic insults in elderly individuals. In response to acute injury conditions, cellular machinery relies on rapid adaptations by modulating posttranslational modifications. Therefore, post-translational regulation of molecular mediators such as hypoxia-inducible factor 1α (HIF-1α), peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), c-MYC, SIRT1 and AMPK play a critical role in the control of the glycolytic-mitochondrial energy axis in response to hypoxic-ischemic conditions. The deficiency of oxygen and nutrients leads to decreased energetic reliance on mitochondria, promoting glycolysis. The combination of pseudohypoxia, declining autophagy, and dysregulation of stress responses with aging adds to impaired host response to hypoxic-ischemic injury. Furthermore, intermitochondrial signal propagation and tissue wide oscillations in mitochondrial metabolism in response to oxidative stress are emerging as vital to cellular energetics. Recently reported intercellular transport of mitochondria through tunneling nanotubes also play a role in the response to and treatments for ischemic injury. In this review we attempt to provide an overview of some of the molecular mechanisms and potential therapies involved in the alteration of cellular energetics with aging and injury with a neurobiological perspective.

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Downregulation of Sirt1 as aging change in advanced heart failure

Cited by 95 publications

References 31 publications

Dietary resveratrol confers apoptotic resistance to oxidative stress in myoblasts

Dietary resveratrol confers apoptotic resistance to oxidative stress in myoblasts

Cardiac metabolism — A promising therapeutic target for heart failure

Mitochondrial function in hypoxic ischemic injury and influence of aging

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