Multiple Levels of PGC-1α Dysregulation in Heart Failure

Oka, Sarang; Sabry, Amira D.; Cawley, Keiko M.; Warren, Jason G.

doi:10.3389/fcvm.2020.00002

Cited by 55 publications

(47 citation statements)

References 155 publications

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“…It is possible that Perm1 helps to accomplish this task by supressing PGC-1α expression at the transcription level, while stabilizing its protein level through PTMs. Futher studies are necessary to fully understand the role of Perm1 in the complex regulation of PGC-1α expression in the heart [42].…”

Section: Plos Onementioning

confidence: 99%

Perm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1

et al. 2020

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The transcriptional regulatory machinery in mitochondrial bioenergetics is complex and is still not completely understood. We previously demonstrated that the histone methyltransferase Smyd1 regulates mitochondrial energetics. Here, we identified Perm1 (PPARGC-1 and ESRR-induced regulator, muscle specific 1) as a downstream target of Smyd1 through RNA-seq. Chromatin immunoprecipitation assay showed that Smyd1 directly interacts with the promoter of Perm1 in the mouse heart, and this interaction was significantly reduced in mouse hearts failing due to pressure overload for 4 weeks, where Perm1 was downregulated (24.4 ± 5.9% of sham, p<0.05). Similarly, the Perm1 protein level was significantly decreased in patients with advanced heart failure (55.2 ± 13.1% of donors, p<0.05). Phenylephrine (PE)-induced hypertrophic stress in cardiomyocytes also led to downregulation of Perm1 (55.7 ± 5.7% of control, p<0.05), and adenovirus-mediated overexpression of Perm1 rescued PE-induced downregulation of estrogen-related receptor alpha (ERRα), a key transcriptional regulator of mitochondrial energetics, and its target gene, Ndufv1 (Complex I). Pathway enrichment analysis of cardiomyocytes in which Perm1 was knocked-down by siRNA (siPerm1), revealed that the most downregulated pathway was metabolism. Cell stress tests using the Seahorse XF analyzer showed that basal respiration and ATP production were significantly reduced in siPerm1 cardiomyocytes (40.7% and 23.6% of scrambled-siRNA, respectively, both p<0.05). Luciferase reporter gene assay further revealed that Perm1 dose-dependently increased the promoter activity of the ERRα gene and known

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Section: Plos Onementioning

confidence: 99%

Perm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1

et al. 2020

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“…Aerobic activity has been shown to decrease adenosine triphosphate (ATP) levels and increase intracellular calcium levels, thereby triggering the activation of the AMPK and CaMK pathways (31). The activation of these pathways results in the activation of MEF2 transcription and increased synthesis of PGC-1a (32). By regulating the expression of both contractile and enzymatic proteins, the working capacity increases, thereby providing the required energy (33).…”

Section: Discussionmentioning

confidence: 99%

The Regulation of the Concentrations of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha and Sirtuin 1 Protein in the Soleus Muscle by Aerobic Exercise Training in Obese Wistar Rats

Hejazi¹,

Hosseini²,

Fathi³

et al. 2020

J Kermanshah Univ Med Sci

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Background: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and Sirtuin 1 (SIRT1) are significant indicators of obesity and other metabolic disorders. Objectives: The present study aimed to investigate the regulation of the concentrations of PGC-1a and SIRT1 protein in the soleus muscle by aerobic exercise training in obese Wistar rats. Methods: This study was conducted on 24 obese male rats, which were randomly categorized into three groups of control, medium-intensity training (28 m/min), and high-intensity training (34 m/min) after obesity induction through a high-fat diet. A series of aerobic trainings in five sessions of 60-minute aerobic training per week was performed for eight weeks. Data analysis was performed using one-way ANOVA to examine the mean differences between the groups. In addition, Tukey’s post-hoc test was used for the paired comparisons of the groups. Results: Significant differences were observed in the concentrations of the PGC-1a (P < 0.001) and SIRT1 proteins between the study groups (P < 0.001). Tukey’s post-hoc test revealed a significant difference between the moderate-intensity aerobic exercise and control groups (P < 0.01) regarding their mean concentration of the PGC-1a protein. However, the high- and moderate-intensity groups showed no difference in this regard (P < 0.028). Moreover, there was a significant difference in the concentration of the SIRT1 protein between the moderate-intensity aerobic exercise and control groups (P < 0.02), and the high-intensity training and control groups (P < 0.005). Conclusions: According to the results, aerobic exercise training could activate SIRT1 and PGC-1a and might enhance mitochondrial biogenesis in the subcutaneous fat. Therefore, aerobic training is recommended as a therapeutic approach to obesity and several other metabolic diseases.

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“…7,48 Regulation of fatty acid oxidation occurs on a transcriptional level with down-regulation of the transcriptional coactivators peroxisome proliferatoractivated receptor gamma coactivator 1 alpha/beta (PGC-1a/b) and their interconnected transcription factors, including peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha, and nuclear respiratory factor 1. 7,49 PGC-1a functions as a master regulator of mitochondrial biogenesis and respiration, and its downregulation is indicative for heart failure progression. 50 This might be the consequence of sustained adrenergic signaling with Akt and/or mTOR activation.…”

Section: Pascal Alexander Mann and Michael Lehrke MDmentioning

confidence: 99%

Cardiac substrate utilization in heart failure: Where is the relevance of SGLT2 inhibition?

Mann

Lehrke

2022

The Journal of Thoracic and Cardiovascular Surgery

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Multiple Levels of PGC-1α Dysregulation in Heart Failure

Cited by 55 publications

References 155 publications

Perm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1

Perm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1

The Regulation of the Concentrations of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha and Sirtuin 1 Protein in the Soleus Muscle by Aerobic Exercise Training in Obese Wistar Rats

Cardiac substrate utilization in heart failure: Where is the relevance of SGLT2 inhibition?

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