Transcriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle.

Laurent Perrin, Ursula Loizides-Mangold, Stéphanie Chanon, Cédric Gobet, Nicolas Hulo, Laura Isenegger, Benjamin D Weger, Eugenia Migliavacca, Aline Charpagne, James A Betts, Jean-Philippe Walhin, Iain Templeman, Keith Stokes, Dylan Thompson, Kostas Tsintzas, Maud Robert, Cedric Howald, Howard Riezman, Jerome N Feige, Leonidas G Karagounis, Jonathan D Johnston, Emmanouil T Dermitzakis, Frédéric Gachon, Etienne Lefai, Charna Dibner

Journal: eLife 2019;7():e34114

PMID: 29658882

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Abstract

Circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. More extensive rhythmic transcription was observed in human skeletal muscle compared to in vitro cell culture as a large part of the in vivo mRNA rhythmicity was lost in vitro. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin-stimulated glucose uptake were significantly reduced upon depletion. Our findings suggest an essential role for the circadian coordination of skeletal muscle glucose homeostasis and lipid metabolism in humans.

Address: Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.; Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.; Institute of Genetics and Genomics of Geneva, Geneva, Switzerland.; CarMeN Laboratory, INSERM U1060, Oullins, France.; Nestlé Institute of Health Sciences, Lausanne, Switzerland.; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.; Institute of Genetics and Genomics of Geneva, Geneva, Switzerland.; Service for Biomathematical and Biostatistical Analyses, Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.; Service for Biomathematical and Biostatistical Analyses, Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.; Nestlé Institute of Health Sciences, Lausanne, Switzerland.; Department for Health, University of Bath, Bath, United Kingdom.; MRC/ARUK Centre for Musculoskeletal Ageing, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.; Department of Digestive and Bariatric Surgery, Edouard Herriot University Hospital, Lyon, France.; Institute of Genetics and Genomics of Geneva, Geneva, Switzerland.; Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.; Department of Biochemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland.; Experimental Myology and Integrative Biology Research Cluster, Faculty of Sport and Health Sciences, University of St Mark and St John, Plymouth, United Kingdom.; Institute of Nutritional Science, Nestlé Research Centre, Lausanne, Switzerland.; Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.

DOI: 10.7554/eLife.34114

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MeSH Terms: CLOCK Proteins, Circadian Clocks, Gene Expression Profiling, Glucose, Humans, Lipid Metabolism, Metabolic Networks and Pathways, Muscle, Skeletal