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

Hodge BA, Wen Y, Riley LA, Zhang X, England JH, Harfmann BD, Schroder EA, Esser KA - Skelet Muscle (2015)

Bottom Line: Within skeletal muscle exists an intrinsic molecular clock mechanism that regulates the timing of physiological processes.We also observed a gene signature indicative of a fast to slow fiber-type shift and a more oxidative skeletal muscle in the iMS-Bmal1 (-/-) model.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, College of Medicine, University of Kentucky, MS 508, 800 Rose Street, Lexington, KY 40536 USA ; Center for Muscle Biology, University of Kentucky, 800 Rose Street, Lexington, KY 40536 USA.

ABSTRACT

Background: 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 a more 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.

No MeSH data available.


Related in: MedlinePlus

Gene ontology analysis of the skeletal muscle circadian transcriptome. Top 15 enriched GO processes listed from left to right in order of significance.
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Fig1: Gene ontology analysis of the skeletal muscle circadian transcriptome. Top 15 enriched GO processes listed from left to right in order of significance.

Mentions: To identify circadian gene expression in skeletal muscle, we used a publicly available, high-resolution, circadian time-course microarray dataset from gastrocnemius muscles of male C57BL/6 mice [45,46]. These mice were housed in constant darkness, and food was provided ad libitum to eliminate the influence of external environmental cues. We chose this dataset because it has double the sampling frequency of previously published circadian muscle transcriptomes, and this allows for greater precision for circadian analysis [46,54]. Using the JTK_CYCLE statistical algorithm [47] for the reliable detection of oscillating transcripts with a 24-h periodicity, we identified 1,628 circadian mRNAs (adjusted P < 0.05). An unbiased Gene Ontology enrichment analysis of these circadian genes revealed a significant overrepresentation of cellular metabolic processes, with approximately 1,004 (62%) genes directly involved in skeletal muscle metabolic processes as well as the regulation of metabolism (Figure 1).Figure 1


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

Hodge BA, Wen Y, Riley LA, Zhang X, England JH, Harfmann BD, Schroder EA, Esser KA - Skelet Muscle (2015)

Gene ontology analysis of the skeletal muscle circadian transcriptome. Top 15 enriched GO processes listed from left to right in order of significance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4440511&req=5

Fig1: Gene ontology analysis of the skeletal muscle circadian transcriptome. Top 15 enriched GO processes listed from left to right in order of significance.
Mentions: To identify circadian gene expression in skeletal muscle, we used a publicly available, high-resolution, circadian time-course microarray dataset from gastrocnemius muscles of male C57BL/6 mice [45,46]. These mice were housed in constant darkness, and food was provided ad libitum to eliminate the influence of external environmental cues. We chose this dataset because it has double the sampling frequency of previously published circadian muscle transcriptomes, and this allows for greater precision for circadian analysis [46,54]. Using the JTK_CYCLE statistical algorithm [47] for the reliable detection of oscillating transcripts with a 24-h periodicity, we identified 1,628 circadian mRNAs (adjusted P < 0.05). An unbiased Gene Ontology enrichment analysis of these circadian genes revealed a significant overrepresentation of cellular metabolic processes, with approximately 1,004 (62%) genes directly involved in skeletal muscle metabolic processes as well as the regulation of metabolism (Figure 1).Figure 1

Bottom Line: Within skeletal muscle exists an intrinsic molecular clock mechanism that regulates the timing of physiological processes.We also observed a gene signature indicative of a fast to slow fiber-type shift and a more oxidative skeletal muscle in the iMS-Bmal1 (-/-) model.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, College of Medicine, University of Kentucky, MS 508, 800 Rose Street, Lexington, KY 40536 USA ; Center for Muscle Biology, University of Kentucky, 800 Rose Street, Lexington, KY 40536 USA.

ABSTRACT

Background: 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 a more 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.

No MeSH data available.


Related in: MedlinePlus