ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency

Xia, Hui; Scholtes, Charlotte; Dufour, Catherine R.; Guluzian, Christina; Giguère, Vincent

doi:10.1016/j.molmet.2023.101814

Cited by 7 publications

(5 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also noted that several of these motifs represent transcription factors normally associated with an acute response to exercise (e.g., ESRRA, NRF1, P53). However, they are not commonly identified as motifs enriched in steady state training induced changes in gene expression [ 10 , [42] , [43] , [44] , [45] , [46] , [47] ], ( Figure 4 E). The results from the DEG motif analysis suggest a very divergent transcriptional mechanism for muscle adaptation with exercise training that relies on inclusion of known acute response pathways.…”

Section: Resultsmentioning

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. 2024

Molecular Metabolism

View full text Add to dashboard Cite

Section: Resultsmentioning

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. 2024

Molecular Metabolism

View full text Add to dashboard Cite

“…We also noted that several of these motifs represent transcription factors normally associated with an acute response to exercise (e.g., ESRRA, NRF1, P53). However, they are not commonly identified as motifs enriched in steady state training induced changes in gene expression [10,43–48], (Figure 3E). The results from the DEG motif analysis suggest a vastly different transcriptional mechanism for muscle adaptation with exercise training that relies on inclusion of known acute response pathways.…”

Section: Resultsmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

“…In another study, a synthetic pan-ERR agonist was shown to induce a transcriptional reprogramming of type IIA muscle fibers as observed in aerobic training and to increase physical endurance in mice [85]. Finally, a recently published study describes how the expression of a mutated form of ERRα, resistant to phosphorylation-induced inactivation, induces muscle fiber aerobic transformation and increases mitochondrial biogenesis, metabolic fuel oxidation, and physical endurance in mice [86].…”

Section: Skeletal Musclementioning

confidence: 94%

Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System

Spinelli,

Bruschi,

Passalacqua

et al. 2024

IJMS

View full text Add to dashboard Cite

The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans. Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts.

show abstract

ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency

Cited by 7 publications

References 73 publications

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

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

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

Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System

Contact Info

Product

Resources

About