ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA906638 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22452372_1.fastq.gz | Fastqsanger.gz | |||
| SRR22452372_2.fastq.gz | Fastqsanger.gz | |||
| SRR22452373_1.fastq.gz | Fastqsanger.gz | |||
| SRR22452373_2.fastq.gz | Fastqsanger.gz | |||
| SRR22452374_1.fastq.gz | Fastqsanger.gz |
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Project description:Objective: Estrogen related receptor α (ERRα) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRα on skeletal muscle exercise metabolism and performance. Methods: We recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRα impedes its degradation, leading to an accumulation of ERRα proteins and perturbation of metabolic homeostasis in ERRα3SA mutant mice. Herein, we used a multi-omics approach in combination with physical endurance tests to ascertain the consequences of expressing the constitutively active phospho-deficient ERRα3SA form on muscle exercise performance and energy metabolism. Results: Genetic heightening of ERRα activity enhanced exercise capacity, fatigue-resistance, and endurance. This phenotype resulted from extensive reprogramming of ERRα global DNA occupancy and transcriptome in muscle leading to an increase in oxidative fibers, mitochondrial biogenesis, fatty acid oxidation, and lactate homeostasis. Conclusion: Our findings support the potential to enhance physical performance and exercise-induced health benefits by targeting molecular pathways regulating ERRα transcriptional activity.
2023-10-11 | GSE219046 | GEO
Project description:ObjectiveEstrogen related receptor α (ERRα) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRα on skeletal muscle exercise metabolism and performance.MethodsWe recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRα impedes its degradation, leading to an accumulation of ERRα proteins and perturbation of metabolic homeostasis in ERRα3SA mutant mice. Herein, we used a multi-omics approach in combination with physical endurance tests to ascertain the consequences of expressing the constitutively active phospho-deficient ERRα3SA form on muscle exercise performance and energy metabolism.ResultsGenetic heightening of ERRα activity enhanced exercise capacity, fatigue-resistance, and endurance. This phenotype resulted from extensive reprogramming of ERRα global DNA occupancy and transcriptome in muscle leading to an increase in oxidative fibers, mitochondrial biogenesis, fatty acid oxidation, and lactate homeostasis.ConclusionOur findings support the potential to enhance physical performance and exercise-induced health benefits by targeting molecular pathways regulating ERRα transcriptional activity.
| S-EPMC10590867 | biostudies-literature
Project description:Mammalian skeletal muscle contains heterogenous myofibers with different contractile and metabolic properties that sustain muscle mass and endurance capacity. The transcriptional regulators that govern these myofiber gene programs have been elucidated. However, the hormonal cues that direct the specification of myofiber types and muscle endurance remain largely unknown. Here we uncover the secreted factor Tsukushi (TSK) as an extracellular signal that is required for maintaining muscle mass, strength, and endurance capacity, and contributes to muscle regeneration. Mice lacking TSK exhibited reduced grip strength and impaired exercise capacity. Muscle transcriptomic analysis revealed that TSK deficiency results in a remarkably selective impairment in the expression of myofibrillar genes characteristic of slow-twitch muscle fibers that is associated with abnormal neuromuscular junction formation. AAV-mediated overexpression of TSK failed to rescue these myofiber defects in adult mice, suggesting that the effects of TSK on myofibers are likely restricted to certain developmental stages. Finally, mice lacking TSK exhibited diminished muscle regeneration following cardiotoxin-induced muscle injury. These findings support a crucial role of TSK as a hormonal cue in the regulation of contractile gene expression, endurance capacity, and muscle regeneration.
2022-01-08 | GSE193089 | GEO
Project description:Subjects Eleven male volunteers (mean age 42.3 + 7.4 years; weight 73.9 + 7.7 kg, height 176.9 + 4.0 cm, body mass index (BMI) 23.6 + 2.1 kg/m2 and body fat: 17.7 + 4.3%) participated in this experiment. They were recruited among experienced ultra-endurance runners and all of them had run at least a race longer than 24 h or 4100 km. On average, they had 15.3 + 7.1 years of training history in running and 7.1 + 4.4 years of ultra-endurance experience. They reported to run an average of 80.5 + 11.7 km/week. Written informed consent was obtained from the subjects. The study was conducted according to the Declaration of Helsinki. The protocol has been approved by the local ethics committee (Comité de Protection des Personnes Sud-Est 1, France) and registered in http:// clinicaltrial.gov (# NCT 00428779). Procedures The subjects visited the laboratory twice, with each session separated by 3–4 weeks. All subjects had run at least three times on a motorized treadmill before taking part in the experiment. In the first session, body mass, height and percentage of body fat (measurements of skin-fold thickness) were measured. The subjects performed a maximal test on a motorized treadmill (Gymrol S2500, HEF Tecmachine, Andrezieux-Boutheon, France), to determine the anaerobic threshold VO2max and the velocity associated with VO2max. The initial velocity was set at 10 km/h and the first stage lasted 6 min. Then, the test consisted of a maximal discontinuous incremental test (slope 50%), where the speed was progressively increased by 1.5 km/h every 3 min, followed by 1 min of rest for the collection of blood samples from the finger tips. The second session consisted of the 24-h treadmill ultra-endurance running protocol (24TR). Subjects were asked to refrain from strenuous exercise for a week before the 24TR. The day of the experiment, all subjects ate the same lunch at noon. About 2 h before starting, a muscle biopsy was taken. Pre-exercise muscle biopsy samples (120 mg) were collected under local anesthesia from the superficial portion of the left vastus lateralis muscle using a percutaneous technique [Henriksson (1979) Acta Neurol Scand 59: 317–323]. A large well-organized fascicle of fibers was oriented and included in an embedding medium (Cryomount; Histolab, Göteborg, Sweden), frozen in isopentane, cooled to its freezing point in liquid nitrogen and stored in liquid nitrogen until further cryostat sectioning. The remaining pieces of the sample were rapidly frozen and stored in liquid nitrogen until protein analyses were performed. After the muscle biopsy procedure, the subjects rested for approximately 2 h and then they were asked to start the 24TR. Ten minutes after the start of the 24TR, subjects were asked to run 4 min at 8 km/h for measurements of running economy (RE). A slow speed was chosen for RE because the average speed over the 24TR was 7.9 + 1.0 km/h, and 8 km/h is representative of the pace over such an extreme exercise [Millet et al. (2009) Scand J Med Sci Sports 21: 54-61]. The food and water intakes during the 24TR were managed by the subjects as in a normal race. Post-exercise muscle biopsy samples (120 mg) were then collected as described above.
2022-05-17 | PXD006840 | Pride
Project description:mTOR and ERRα are key regulators of common metabolic processes. However, the extent of functional overlap between these two factors has not been investigated. ChIP-sequencing analyses on mouse liver reveal mTOR recruitment to regulatory regions of genes on a genome-wide scale including enrichment at genes shared with ERRα that are involved in the TCA cycle and lipogenesis pathway. A total of 9469 and 23226 peaks were identified for mTOR and ERRα ChIP-seq datasets, respectively. mTOR and ERRα mouse liver ChIP-seq datasets obtained from pooling 8 individual ChIPs from a chromatin pool of 26 livers.
2013-04-03 | E-GEOD-43638 | biostudies-arrayexpress
Project description:Objective Estrogen-related-receptor α (ERRα) plays a critical role in the transcriptional regulation of cellular bioenergetics and metabolism, and perturbations in its activity have been associated with metabolic diseases. While several coactivators and corepressors of ERRα have been identified to date, a knowledge gap remains in understanding the extent to which ERRα cooperates with coregulators in the control of gene expression. Herein, we mapped the primary chromatin-bound ERRα interactome in mouse liver. Methods RIME (Rapid Immuno-precipitation Mass spectrometry of Endogenous proteins) analysis using mouse liver samples from two circadian time points was used to catalog ERRα-interacting proteins on chromatin. The genomic crosstalk between ERRα and its identified cofactors in the transcriptional control of precise gene programs was explored through cross-examination of genome-wide binding profiles from chromatin immunoprecipitation-sequencing (ChIP-seq) studies. The dynamic interplay between ERRα and its newly uncovered cofactor Host cell factor C1 (HCFC1) was further investigated by loss-of-function studies in hepatocytes. Results Characterization of the hepatic ERRα chromatin interactome led to the identification of 48 transcriptional interactors of which 42 were previously unknown including HCFC1. Interrogation of available ChIP-seq binding profiles highlighted oxidative phosphorylation (OXPHOS) under the control of a complex regulatory network between ERRα and multiple cofactors. While ERRα and HCFC1 were found to bind to a large set of common genes, only a small fraction showed their co-localization, found predominately near the transcriptional start sites of genes particularly enriched for components of the mitochondrial respiratory chain. Knockdown studies demonstrated inverse regulatory actions of ERRα and HCFC1 on OXPHOS gene expression ultimately dictating the impact of their loss-of-function on mitochondrial respiration. Conclusions Our work unveils a repertoire of previously unknown transcriptional partners of ERRα comprised of chromatin modifiers and transcription factors thus advancing our knowledge of how ERRα regulates metabolic transcriptional programs.
2024-06-22 | PXD047767 | Pride
Project description:The peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) coordinates the transcriptional network response to promote an improved endurance capacity in skeletal muscle, e.g. by co-activating the estrogen-related receptor α (ERRα) in the regulation of oxidative substrate metabolism. Despite a close functional relationship, the interaction between these two proteins has not been studied on a genomic level. We now mapped the genome-wide binding of ERRα to DNA in skeletal muscle cell line with elevated PGC-1α and linked the DNA recruitment to global PGC-1α target gene regulation. We found that, surprisingly, ERRα co-activation by PGC-1α is only observed in the minority of all PGC-1α recruitment sites. Nevertheless, a majority of PGC-1α target gene expression is dependent on ERRα. Intriguingly, the interaction between these two proteins is controlled by the genomic context of response elements, in particular the relative GC and CpG content, monomeric and dimeric repeat binding site configuration for ERRα, and adjacent recruitment of the transcription factor SP1. These findings thus not only reveal an unprecedented insight into the regulatory network underlying muscle cell plasticity, but also strongly link the genomic context of DNA response elements to control transcription factor - co-regulator interactions.
2016-04-22 | GSE80521 | GEO
Project description:The peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) coordinates the transcriptional network response to promote an improved endurance capacity in skeletal muscle, e.g. by co-activating the estrogen-related receptor α (ERRα) in the regulation of oxidative substrate metabolism. Despite a close functional relationship, the interaction between these two proteins has not been studied on a genomic level. We now mapped the genome-wide binding of ERRα to DNA in skeletal muscle cell line with elevated PGC-1α and linked the DNA recruitment to global PGC-1α target gene regulation. We found that, surprisingly, ERRα co-activation by PGC-1α is only observed in the minority of all PGC-1α recruitment sites. Nevertheless, a majority of PGC-1α target gene expression is dependent on ERRα. Intriguingly, the interaction between these two proteins is controlled by the genomic context of response elements, in particular the relative GC and CpG content, monomeric and dimeric repeat binding site configuration for ERRα, and adjacent recruitment of the transcription factor SP1. These findings thus not only reveal an unprecedented insight into the regulatory network underlying muscle cell plasticity, but also strongly link the genomic context of DNA response elements to control transcription factor - co-regulator interactions.
2016-04-22 | GSE80520 | GEO
Project description:Running at different times of the day resulted in a vastly different activation of signaling pathways, e.g., related to stress response, vesicular trafficking, repair, and regeneration. Second, voluntary wheel running at the opposite phase of the dark, feeding period surprisingly revealed minimal Zeitgeber (i.e., synchronizing) activity of training. This integrated study provides important insights into the circadian regulation of endurance performance and the control of the circadian clock by exercise.
2021-06-16 | GSE178262 | GEO
Project description:Divergent skeletal muscle phenotypes result from chronic resistance-type versus endurance-type contraction, reflecting the principle of training specificity. However, it is unclear whether there is a common set of genetic factors that influence skeletal muscle adaptation to disuse. Female rats were obtained from out-bred lines selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n=6/group; generation 19). Both groups underwent 3 d of hindlimb immobilization to induce atrophy of the plantaris and soleus muscles prior to comparison to non-immobilization controls of the same genotype. RNA sequencing was performed to identify Gene Ontology Biological Processes with differential (LRT vs HRT) gene set enrichment. Running distance, determined well in advance of hindlimb immobilization, increased in response to aerobic training in HRT but not LRT. The atrophy response to hindlimb immobilization was exaggerated in LRT versus HRT. There were between-group differences for 140 processes in plantaris muscle and 118 processes in soleus muscle. In conclusion, low responders to aerobic endurance training exhibited exaggerated atrophy, and this was associated with differential gene expression. Thus, our findings suggest that genetic factors that underpin aerobic training maladaptation may also dysregulate the transcriptional activity of biological processes that contribute to adaptation to hindlimb immobilization.
2021-10-24 | GSE159861 | GEO