The endogenous molecular clock orchestrates the temporal separation of substrate metabolism in skeletal muscle

Brian A. Hodge, Yuan Wen, Lance A. Riley, Xiping Zhang, Jonathan H. England, Brianna D. Harfmann, Elizabeth A. Schroder, Karyn A. Esser

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


Skeletal muscle is a major contributor to whole-body metabolism as it serves as a depot for both glucose and amino acids, and is a highly metabolically active tissue. Within skeletal muscle exists an intrinsic molecular clock mechanism that regulates the timing of physiological processes. A key function of the clock is to regulate the timing of metabolic processes to anticipate time of day changes in environmental conditions. The purpose of this study was to identify metabolic genes that are expressed in a circadian manner and determine if these genes are regulated downstream of the intrinsic molecular clock by assaying gene expression in an inducible skeletal muscle-specific Bmal1 knockout mouse model (iMS-Bmal1-/-). Methods: We used circadian statistics to analyze a publicly available, high-resolution time-course skeletal muscle expression dataset. Gene ontology analysis was utilized to identify enriched biological processes in the skeletal muscle circadian transcriptome. We generated a tamoxifen-inducible skeletal muscle-specific Bmal1 knockout mouse model and performed a time-course microarray experiment to identify gene expression changes downstream of the molecular clock. Wheel activity monitoring was used to assess circadian behavioral rhythms in iMS-Bmal1 -/- and control iMS-Bmal1+/+ mice. Results: The skeletal muscle circadian transcriptome was highly enriched for metabolic processes. Acrophase analysis of circadian metabolic genes revealed a temporal separation of genes involved in substrate utilization and storage over a 24-h period. A number of circadian metabolic genes were differentially expressed in the skeletal muscle of the iMS-Bmal1 -/- mice. The iMS-Bmal1-/- mice displayed circadian behavioral rhythms indistinguishable from iMS-Bmal1+/+ mice. We also observed a gene signature indicative of a fast to slow fiber-type shift and amore oxidative skeletal muscle in the iMS-Bmal1 -/- model. Conclusions: These data provide evidence that the intrinsic molecular clock in skeletal muscle temporally regulates genes involved in the utilization and storage of substrates independent of circadian activity. Disruption of this mechanism caused by phase shifts (that is, social jetlag) or night eating may ultimately diminish skeletal muscle's ability to efficiently maintain metabolic homeostasis over a 24-h period.

Original languageEnglish
Article number17
JournalSkeletal Muscle
Issue number1
StatePublished - May 16 2015

Bibliographical note

Funding Information:
The authors would wish to thank John Hogenesch for providing the skeletal muscle circadian transcriptome data. We would like to thank John McCarthy for his intellectual support in the analysis of the data. We would like to thank Tanya Seward for the breeding and maintaining of mouse colonies. We would like to thank Trusha Mehta for contributing with the collection and analysis of the mouse activity data. We would like to thank Donna Wall and the Microarray Core Facility at the University of Kentucky for performing the microarray experiments. This work was supported by funding from the National Institutes of Health, NIH AR066082.

Publisher Copyright:
© 2015 Hodge et al.


  • Anabolic
  • Bmal1
  • Catabolic
  • Circadian
  • Metabolism
  • Molecular clock
  • Rev-erbα
  • Skeletal muscle
  • Temporal separation

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Molecular Biology
  • Cell Biology


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