Physical Exercise Regulates p53 Activity Targeting SCO2 and Increases Mitochondrial COX Biogenesis in Cardiac Muscle with Age

Qi, Zhengtang; He, Jing; Su, Yiwei; He, Qing; Liu, Jingxia; Yu, Lu; Al‐Attas, Omar S.; Hussain, Tajamul; Ding, Shuzhe; Liu, Ji; Qian, Min

doi:10.1371/journal.pone.0021140

Cited by 34 publications

(24 citation statements)

References 62 publications

(77 reference statements)

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“…A recent study has demonstrated that low-intensity interval exercise training decreases calcium-induced mitochondrial permeability transition in aortic-banded miniature swine [2], which may positively affect cytosolic systems. In addition, exercise training has been shown to improve cardiac redox balance in young and old healthy animals [23], [50]. We extended these findings by showing that 8 weeks of aerobic exercise training restored oxidative phosphorylation efficiency along with a reduction in H 2 O 2 release and increased maximum calcium uptake in isolated mitochondria from myocardial infarction-induced heart failure rats.…”

Section: Discussionmentioning

confidence: 62%

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

et al. 2012

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Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H2O2 release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H2O2 resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca2+-induced permeability transition and reduced H2O2 release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a non-pharmacological tool for heart failure therapy.

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Section: Discussionmentioning

confidence: 62%

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

et al. 2012

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“…Among the thirteen subunits of COX, the largest subunits, COX I–III, are encoded by the mtDNA and regulated at the transcriptional level by T-fam (45). COX is the terminal enzyme of the electron transport chain and plays a pivotal role in electron transfer to molecular oxygen and generation and maintenance of ΔΨm and ATP.…”

Section: Discussionmentioning

confidence: 99%

TLR4-Mediated AKT Activation Is MyD88/TRIF Dependent and Critical for Induction of Oxidative Phosphorylation and Mitochondrial Transcription Factor A in Murine Macrophages

Bauerfeld

Rastogi

Pirockinaite

et al. 2012

The Journal of Immunology

103

157

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Mitochondria play a critical role in cell survival and death. Mitochondrial recovery during inflammatory processes such as sepsis is associated with cell survival. Recovery of cellular respiration, mitochondrial biogenesis and function requires coordinated expression of transcription factors encoded by nuclear and mitochondrial genes, including mitochondrial transcription factor A (T-fam) and cytochrome c oxidase (COX, complex IV). LPS elicits strong host defenses in mammals with pronounced inflammatory responses but also triggers activation of survival pathways such as AKT pathway. AKT/PKB is a serine/threonine protein kinase playing an important role in cell survival, protein synthesis, and controlled inflammation in response to TLRs. Hence, we investigated the role of LPS mediated AKT activation in mitochondrial bioenergetics and function in cultured murine macrophages (B6-MCL) and bone marrow derived macrophages. We show that LPS challenge led to increased expression of T-fam and COX subunit I and IV in a time dependent manner through early phosphorylation of the PI3kinase/AKT pathway. PI3K/AKT pathway inhibitors abrogated LPS mediated T-fam and COX induction. Lack of induction was associated with decreased ATP production, increased proinflammatory cytokines (TNF-α), nitric oxide production and cell death. The TLR4 mediated AKT activation and mitochondrial biogenesis required activation of adaptor protein MyD88 and Toll-IL-1R-containing adaptor inducing IFN-β (TRIF). Importantly, using a genetic approach, we show that the AKT1 isoform is pivotal in regulating mitochondrial biogenesis in response to TLR4 agonist.

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“…In addition to its roles in DNA damage repair, cell cycle, and apoptosis, p53 has been shown to regulate cellular respiration and metabolism, while modulating the balance between mitochondrial respiration and glycolytic pathways. [44][45][46] Since p53 expression was comparable between 2 M CA and 18 M CA, we further sought to investigate the age-related changes in mitochondrial gene expression and deletion as well as the mitochondrial ultrastructure and cytochrome C oxidase activity.…”

Section: Discussionmentioning

confidence: 99%

Rejuvenation of Cardiac Tissue Developed from Reprogrammed Aged Somatic Cells

Cheng

Peng

Zhang

et al. 2017

Rejuvenation Research

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Induced pluripotent stem cells (iPSCs) derived via somatic cell reprogramming have been reported to reset aged somatic cells to a more youthful state, characterized by elongated telomeres, a rearranged mitochondrial network, reduced oxidative stress, and restored pluripotency. However, it is still unclear whether the reprogrammed aged somatic cells can function normally as embryonic stem cells (ESCs) during development and be rejuvenated. In the current study, we applied the aggregation technique to investigate whether iPSCs derived from aged somatic cells could develop normally and be rejuvenated. iPSCs derived from bone marrow myeloid cells of 2-month-old (2 M) and 18-month-old (18 M) C57BL/6-Tg (CAG-EGFP)1Osb/J mice were aggregated with embryos derived from wild-type ICR mice to produce chimeras (referred to as 2 M CA and 18 M CA, respectively). Our observations focused on comparing the ability of the iPSCs derived from 18 M and 2 M bone marrow cells to develop rejuvenated cardiac tissue (the heart is the most vital organ during aging). The results showed an absence of p16 and p53 upregulation, telomere length shortening, and mitochondrial gene expression and deletion in 18 M CA, whereas slight changes in mitochondrial ultrastructure, cytochrome C oxidase activity, ATP production, and reactive oxygen species production were observed in CA cardiac tissues. The data implied that all of the aging characteristics observed in the newborn cardiac tissue of 18 M CA were comparable with those of 2 M CA newborn cardiac tissue. This study provides the first direct evidence of the aging-related characteristics of cardiac tissue developed from aged iPSCs, and our observations demonstrate that partial rejuvenation can be achieved by reprogramming aged somatic cells to a pluripotent state.

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Physical Exercise Regulates p53 Activity Targeting SCO2 and Increases Mitochondrial COX Biogenesis in Cardiac Muscle with Age

Cited by 34 publications

References 62 publications

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

TLR4-Mediated AKT Activation Is MyD88/TRIF Dependent and Critical for Induction of Oxidative Phosphorylation and Mitochondrial Transcription Factor A in Murine Macrophages

Rejuvenation of Cardiac Tissue Developed from Reprogrammed Aged Somatic Cells

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