Metabolism and exercise: the skeletal muscle clock takes centre stage

Martin, Ryan A.; Viggars, Mark; Esser, Karyn A.

doi:10.1038/s41574-023-00805-8

Cited by 24 publications

(13 citation statements)

References 105 publications

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“…As a start we identified 1217 differentially expressed genes (DEGs; q < 0.05) between the sedentary control vs. sedentary iMSBmal1 KO mice; 535 that were upregulated and 682 that were downregulated with muscle specific Bmal1 knockout respectively. As seen in the volcano plot (Supplementary Figure 4A) and consistent with prior studies[5,8,9,28], many of the clock output genes, such as Dbp , Ppargc1a (Pgc1a) , Mylk4 , and Tcap were significantly down-regulated[34,35]. Motif analysis of the promoters of the 682 down-regulated genes determined that there was significant enrichment for E-boxes, and these include several circadian clock (CLOCK, NPAS2) specific E-boxes, as well as MYC specific E-box sequences.…”

Section: Resultssupporting

confidence: 91%

“…Subsequent KEGG pathway analysis of the DEGs confirmed significant dysregulation of genes associated with 'circadian rhythms' (14 genes), as well as a large number of pathways relating to substrate metabolism, (Supplementary Figure 6C). Within this pathway, we identified dysregulation of transcripts essential for glucose and glycogen homeostasis including (Hk2, Rab10, Slc2a3, Slc2a4, Tbc1d1, Aldoc, Fbp2, Gbe1, Pgm1, Pgm2, Phka1, Pygm) as previously reported [4][5][6].…”

Section: Resultssupporting

confidence: 66%

“…The daily gene expression program regulated by the clock mechanism, called clock output, contributes to temporal patterning of a wide range of biological processes including skeletal muscle metabolism and proteostasis [4], as we and others have previously published [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…While it is clear that exercise and the skeletal muscle circadian TTFL are inextricably linked [28], the role, if any, a functional skeletal muscle clock has on skeletal muscle adaptation to exercise has yet to be elucidated. Here we assess the importance of the endogenous skeletal muscle TTFL for exercise adaptation through ablation of Bmal1 expression in adult myofibers, essentially terminating the core circadian TTFL [5].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Over the past decades, the cellular and molecular effects of physical activity on skeletal muscle and the rest of the body have been investigated thoroughly and it has become evident that nearly every known aspect of this physiological response is intertwined with circadian rhythmicity ( 11 ). Bennet and Sato reviewed the current understanding of how exercise as an external cue is integrated with these internal circadian physiological processes to maintain metabolic homeostasis, identifying the opportunity to further research the role of “exerkines” (exercise-induced signaling molecules) and transcription factors that may constitute pharmacological targets.…”

Section: Exercise Timing In Cardiometabolic Healthmentioning

confidence: 99%