Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

Li, Chen; Ma, Nan; Gu, Chengxiong; Liu, Manling; Yang, Zuozhang; Yin, Yulong; Chen, Mai; Wang, Yishi; Han, Yuehu; Yu, Lu; Ma, Heng

doi:10.1111/acel.13096

Cited by 58 publications

(50 citation statements)

References 40 publications

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“…Results concerning LC3-II are less clear. With regard to C57BL/6J mice: (i) LC3II / GAPDH (Taneike et al, 2010) and LC3II / LC3I (Hua et al, 2011; Ren et al, 2017) declined in hearts from ∼ 26 mo vs. ∼ 4 mo animals; (ii) LC3II / LC3I increased in 18 mo vs. 2 mo mice; (Boyle et al, 2011) and (iii) LC3II / LC3I was not different between ∼ 23 mo and ∼ 4 mo animals (Li et al, 2020; Wu et al, 2016). We observed increased LC3I:GAPDH, LC3II:GAPDH, and p62:GAPDH in older vs. adult mice from two independent cohorts treated identically (Figure 1, Figure 3).…”

Section: Discussionmentioning

confidence: 97%

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Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts

Cho

Ramous

et al. 2021

Preprint

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There is evidence for a progressive decline of protein quality control mechanisms during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy (referred to as autophagy) is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24-month old male C57BL/6J mice (old) exhibited : (i) repressed autophagosome formation and protein aggregate accumulation in the heart; (ii) systolic and diastolic dysfunction; and (iii) reduced exercise capacity, vs. 8-month old (adult) mice (all p< .05). Separate cohorts of 21 month old mice completed a 3-month progressive resistance treadmill-running program (old-ETR) that improved (all < .05) : (i) body composition; (ii) exercise capacity; and (iii) soleus muscle citrate synthase activity, vs. age-matched mice that did not train (old-SED). Importantly, (iv) protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) overall function was enhanced (all p<0.05), in hearts from old-ETR vs. old-SED mice. Dietary maneuvers and pharmacological interventions shown to elevate basal autophagy are reported to mitigate / reverse age-associated cardiac dysfunction. Here we show the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and overall function in mouse hearts.

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Section: Discussionmentioning

confidence: 97%

“…A variety of studies indicate p62 accumulates in hearts from aged vs. adult mice (Li et al, 2020; Ren et al, 2017; Wang et al, 2018; Wu et al, 2016; Y. Zhang et al, 2017), and translational relevance of these findings to older humans was recently reported (Li et al, 2020). Results concerning LC3-II are less clear.…”

Section: Discussionmentioning

confidence: 99%

Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts

Cho

Ramous

et al. 2021

Preprint

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“…Because treatment of diabetic OVE26 mice with metformin activated AMPK and increased autophagy [132], interest sparked with regard to using this compound in the context of cardiac aging. As thought, metformin treatment enhanced contractile function and reduced cardiac fibrosis induced by isoproterenol [133], and protected mice from age-induced ischemic necroptosis [134]. Providing translational relevance, metformin reduced the incidence of age-related cardiovascular disease in type 2 diabetic men [135].…”

Section: Pharmacological and Nutraceutical Interventionsmentioning

confidence: 87%

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Ghosh

Vinod

Symons

et al. 2020

Cells

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Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.

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“…According to these reports, autophagic flux was suppressed as the RIPK1–RIPK3 interaction and necroptosis were induced by the combined treatment with TNFα and a broad-spectrum caspase inhibitor (Ogasawara et al, 2017 ); improving autophagic flux through inhibition of mTORC1 was able to attenuate the necroptosis in an autophagy- and transcription factor EB (TFEB; a master regulator of the ALP)-dependent fashion (Ogasawara et al, 2017 ; Abe et al, 2019 ); and MPT was not important in the execution of necroptosis (Ogasawara et al, 2017 ). More recently, Li C. et al ( 2020 ) reported that aging-associated impairment of autophagy promoted myocardial I-R injury, the protection of metformin against such injury was associated with improving autophagic flux, and the upregulation of p62 resulting from decreased autophagy promoted the interaction of RIPK1 and RIPK3, a key step for the activation of the RIPK1–RIPK3-mediated necroptotic pathway. Given that both necroptosis and autophagic impairment have been shown as mediators in cardiac pathogenesis, it will be extremely important to improve our understanding of the interaction between autophagy and necroptosis in cardiomyocytes as the resultant mechanistic insight is expected to help identify potentially new therapeutic strategies to treat a large subset of heart disease.…”

Section: Interactions Between Macroautophagy and The Ripk1–ripk3–mlkl Pathwaysmentioning

confidence: 99%

Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes

2021

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Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin–proteasome system (UPS) but also the autophagic–lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1–RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

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Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

Cited by 58 publications

References 40 publications

Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts

Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes

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