A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity

Billon, Cyrielle; Banerjee, Subhashis; Situala, Sadichha; Welch, Ryan D.; Hegazy, Lamees; Elgendy, Bahaa; Oh, Tae Gyu; Kazantzis, Melissa; Chatterjee, Arindam; Chrivia, John C.; Hayes, Matthew; Xu, Weiyi; Hamilton, Angela; Huss, Jan; Zhang, Lilei; Walker, John K.; Downes, Michael; Evans, Ronald M.; Burris, Thomas P.

doi:10.1101/2022.10.05.510974

Cited by 6 publications

(11 citation statements)

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“…Given that ERRα and ERRγ share many common target genes, 11 it is somewhat surprising that ERRγ is responsible for most of the 332- or 915-induced metabolic gene transcription. 21 Previous studies showed that all ERR isoforms exhibit a basal level of transcriptional activity independent of ligand binding. 109–114 ERR isoforms may have different levels of basal activity resulting in differentially inducible activity by ERR agonists.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we report the cardioprotective effect of a recently described pan-ERR agonist SLU-PP-332 (332) 21 and another structurally distinct pan-ERR agonist SLU-PP-915 (915) in pressure overload–induced HF. Our data show that 332/915, mainly through ERRγ, activated a broad spectrum of metabolic genes, enhanced fatty acid metabolism and mitochondrial function, and improved contractile function in transaortic constriction (TAC)–induced HF in vivo.…”

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confidence: 99%

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Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

Xu,

Billon,

et al. 2024

Circulation

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BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available. METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload–induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity. RESULTS: Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload–induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes. CONCLUSIONS: ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload–induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

Xu,

Billon,

et al. 2024

Circulation

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“…Within the genes upregulated by exercise training in the iMSBmal1KO mouse, motif enrichment analysis included transcription factors sites such as YY1, ESRRA/B, SP1, NRF/1, SMAD2/4 and P53. While many of these represent transcription factors normally associated with an acute response to exercise (e.g., ESRRA, NRF1, P53) they are not commonly identified as motifs enriched in steady state changes in gene expression [37][38][39][40][41][42], (Figure 3E). ESRRA is also known to promote aerobic transformation and increase metabolic fuel efficiency in skeletal muscle, as well as enhances lactate clearance by augmenting its oxidation to pyruvate.…”

Section: 1mentioning

confidence: 99%

Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training

Viggars,

Berko,

Hesketh

et al. 2023

Preprint

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Objective: The skeletal muscle circadian clock plays a pivotal role in muscle homeostasis and metabolic flexibility. Recently, this clock mechanism has been linked to both transcriptional and metabolic responses to acute exercise. However, the contribution of the circadian clock mechanism to the molecular and phenotypic adaptations to exercise training have not been defined. Methods: Inducible skeletal muscle-specific Bmal1-floxed mice were treated with tamoxifen to induce skeletal muscle specific deletion of Bmal1 (iMSBmal1KO) or given a vehicle. Mice were assigned to normal cage conditions, or 6-weeks of progressive treadmill training. Exercise performance, body composition, and tissue/serum indices of metabolic health were assessed over the timecourse of training. Gastrocnemius muscles were collected 48-hours after their last exercise bout for histological, biochemical, and molecular analyses including RNA-sequencing and untargeted metabolomics. Results: Improvements in exercise workload and maximal performance were comparable between iMSBmal1KO mice and vehicle treated controls after 6-weeks of exercise training. However, exercise training in the absence of Bmal1 was not able to rescue the metabolic phenotype and hyperinsulinemia of the iMSBmal1KO mice, attributed to the continued dysregulation of core clock components and gene expression relating to glucose metabolism. Importantly, a much larger and divergent transcriptional reprogramming occurred in the muscle of iMSBmal1KO mice in comparison to their vehicle treated counterparts. This response included a large compensatory upregulation of genes associated with fatty acid β-oxidation, pyruvate metabolism, citric acid cycle components and oxidative phosphorylation components, including mitochondrial subunits and mitoribosome units. Conclusions: Collectively, we propose that endurance training requires muscle Bmal1, and the core clock network, to elicit well recognized molecular adaptations. In the absence of Bmal1, exercise training results in a much larger and divergent re-networking of the basal skeletal muscle transcriptome and metabolome. We also demonstrate that skeletal muscle Bmal1 is indispensable for the transcriptional regulation of glucose homeostasis, even after a 6-weeks exercise training programme.

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“…20,21 We recently described two novel high affinity ERR agonists (SLU-PP-332 and SLU-PP-915) that have sufficient pharmacokinetic properties to use in animal models of disease. 22,23 Recently, we found that treatment of mice with heart failure with these ERR agonists improved cardiac function and noted a substantial increase in expression of genes in the autophagy pathway. 23 Furthermore, we observed that SLU-PP-915 increases autophagic flux in neonatal rat ventricular myocytes (NRVMs).…”

Section: Introductionmentioning

confidence: 99%

“…20,21 We recently described two novel high affinity ERR agonists (SLU-PP-332 and SLU-PP-915) that have sufficient pharmacokinetic properties to use in animal models of disease. 22,23 SLU-PP-332 has an EC50 of 98 nM with ERRα, 230 nM ERRβ, and 430 nM ERRγ providing for a degree of alpha selective, while SLU-PP-915 has EC 50 values of approximately 400 nM for each.…”

Section: Introductionmentioning

confidence: 99%

The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB

Losby

Hayes

Valfort

et al. 2023

Preprint

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Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) play fundamental role in regulation of cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy in cardiomyocytes. Here, we characterized a mechanism by which ERRs induce autophagy in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be important in cardiac autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12myoblasts. ERR-dependent increases in TFEB expression results in increased expression of an array of TFEB target genes, which are critical for stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for treatment of many diseases where stimulation of autophagy may be therapeutic including heart failure.

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A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity

Cited by 6 publications

References 64 publications

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training

The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB

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