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Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

ABSTRACT: Background: A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. Methods: ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). Pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. Results: Remarkably, only an 8-week treatment with the pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression. Conclusions: Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE154050 | GEO | 2020/07/09

REPOSITORIES: GEO

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ERR agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Project description:A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction, and inflammation, which collectively contribute to age-related kidney disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs are decreased in aging human and mouse kidneys and preserved in aging mice with lifelong caloric restriction (CR). Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. ERRα, ERRβ, and ERRγ levels are decreased in the aging kidney. Remarkably, only a 4-week treatment of 21-month-old mice with the pan ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and Mcad expression.

2023-08-02 | PXD020051 | Pride

Effect of deletion of ERRalpha, ERRbeta and/or ERRgamma on gene expression in soleus and extensor digitorum longus (EDL) skeletal muscles

Project description:The three estrogen related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle have not been elucidated. To address the roles and significance of ERRs for skeletal muscle mitochondria and muscle function, we generated mice lacking combinations of ERRs specifically in skeletal muscle. We then compared the impact of ERR loss on the transcriptomes of EDL and soleus, i.e., muscles rich in glycolytic or oxidative fibers, respectively. Our findings highlight an essential role of ERRs for skeletal muscle oxidative metabolism and identify broad classes of ERR-dependent gene programs in muscle. They also suggest a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, with ERR isoform-specific phenotypes being driven primarily, but not exclusively, by their relative levels in different muscles. To compare the relative contributions of ERRs for oxidative capacity in glycolytic and oxidative skeletal muscles, we generated mice lacking one or two ERRs specifically in skeletal muscle. We then performed gene expression profiling analysis using data obtained from RNA-seq of soleus and EDL muscles of WT and ERR KO mice .

2023-01-09 | GSE214876 | GEO

Mitofusin 2 expression in muscle decreases during aging and generates a gene signature characteristic of aged muscle

Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness. Quadriceps muscle from four mice per genotype were used (Control young (6 month-old), Mfn2KO young (6-month-old), control old (22-month-old) and Mfn2KO old (22-month-old)

2016-08-08 | E-GEOD-71501 | biostudies-arrayexpress

NAD+ supplementation counteracts senescence mediated by STING in Ataxia Telangiectasia models by improving mitophagy (Human)

Project description:Senescence phenotypes and mitochondrial dysfunction are implicated in aging and neurodegeneration, and in the premature aging disease, including A-T. Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. Here we demonstrate impaired mitochondrial function and increased senescence growth arrest with senescence-associated secretory phenotype (SASP) in A-T patient fibroblasts, and in ATM-deficient cells and mice. We find that boosting intracellular NAD+ levels with nicotinamide riboside (NR) reduces senescence, suppresses neuroinflammation, and improves motor function in Atm-/- mice. We further show that the senescence responses are mediated by stimulator of interferon genes (STING), which is activated by cytoplasmic mtDNA and that NR prevents senescence and neuroinflammation through stimulation of mitophagy. Our findings suggest a pivotal role for mitochondrial dysfunction induced senescence in A-T pathogenesis, and that enhancing mitophagy is a potential therapeutic intervention.

2021-05-25 | GSE152287 | GEO

NAD+ supplementation counteracts senescence mediated by STING in Ataxia Telangiectasia models by improving mitophagy (Mouse)

2021-05-25 | GSE152286 | GEO

Resistance Exercise Reverses Aging in Human Skeletal Muscle

Project description:Human aging is associated with skeletal muscle atrophy and functional impairment (sarcopenia). Multiple lines of evidence suggest that mitochondrial dysfunction is a major contributor to sarcopenia. We evaluated whether healthy aging was associated with a transcriptional profile reflecting mitochondrial impairment and whether resistance exercise could reverse this signature to that approximating a younger physiological age. Skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women were compared using gene expression profiling, and a subset of these were related to measurements of muscle strength. 14 of the older adults had muscle samples taken before and after a six-month resistance exercise-training program. Before exercise training, older adults were 59% weaker than younger, but after six months of training in older adults, strength improved significantly (P<0.001) such that they were only 38% lower than young adults. As a consequence of age, we found 596 genes differentially expressed using a false discovery rate cut-off of 5%. Prior to the exercise training, the transcriptome profile showed a dramatic enrichment of genes associated with mitochondrial function with age. However, following exercise training the transcriptional signature of aging was markedly reversed back to that of younger levels for most genes that were affected by both age and exercise. We conclude that healthy older adults show evidence of mitochondrial impairment and muscle weakness, but that this can be partially reversed at the phenotypic level, and substantially reversed at the transcriptome level, following six months of resistance exercise training. Keywords: resistance exercise, muscle, aging

2007-07-16 | GSE8479 | GEO

Mitofusin 2 expression in muscle decreases during aging and generates a gene signature characteristic of aged muscle

2016-08-08 | GSE71501 | GEO

Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

Project description:Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRalpha and ERRgamma are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential theraputic intervention for heart failure. However, in vivo studies demonstrating the potential utility of ERR agonists for heart failure treatment are lacking, as compounds with pharmackinetics appropriate for in vivo use have not been available. Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction, ameliorated fibrosis and increased survival associated with pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particulary genes involved in fatty acid metabolism and mitochondrial function. Using both in vitro and in vivo genetic dependency experiments, we show that ERRgamma is the main mediatorof ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. Additionally, ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo. Our results provide direct pharmacological evidence supporting the further in vivo development of ERR agonists as novel heart failure theraputics.

2024-01-01 | GSE241075 | GEO

Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

2023-11-21 | GSE239912 | GEO

Skeletal Muscle Transcript Profiles in Trained or Sedentary Young and Old Subjects

Project description:Aging is associated with mitochondrial dysfunction and insulin resistance. We conducted a study to determine the role of long-term vigorous endurance exercise on age-related changes in insulin sensitivity and various indices of mitochondrial functions. Keywords: The effect of excises in young and old human subjects by transcription profiling

2007-11-01 | GSE9103 | GEO

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