Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock
| Autor: | Thomas O. Eichmann, Mattia Albiero, Alberto Casarin, Michaël Jean Hubert, Vanessa Pertegato, Maximilian Kleinert, Katrin Fischer, Fabiana Quagliarini, Bert Blaauw, Vanina Romanello, S. Mazzucco, Ashfaq Ali Mir, Franziska Greulich, Rosario Rizzuto, Gianni Biolo, Dominik Lutter, Stefano Schiaffino, Leonardo Salviati, Marcia Ivonne Peña Paz, Stefano Ciciliot, Lauren E. Wright, Kenneth A. Dyar, N. Henriette Uhlenhaut |
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| Přispěvatelé: | Dyar, K. A., Hubert, M. J., Mir, A. A., Ciciliot, S., Lutter, D., Greulich, F., Quagliarini, F., Kleinert, M., Fischer, K., Eichmann, T. O., Wright, L. E., Pena Paz, M. I., Casarin, A., Pertegato, V., Romanello, V., Albiero, M., Mazzucco, S., Rizzuto, R., Salviati, L., Biolo, G., Blaauw, B., Schiaffino, S., Uhlenhaut, N. H. |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Messenger Circadian clock Protein metabolism CLOCK Proteins Muscle Proteins Gene Expression Protein Synthesis Biochemistry Energy homeostasis chemistry.chemical_compound Mice 0302 clinical medicine Medicine and Health Sciences Homeostasis Biology (General) Amino Acids Musculoskeletal System Protein Metabolism Mice Knockout General Neuroscience Muscles Circadian Clock Methods and Resources ARNTL Transcription Factors Chemical Synthesis Skeletal 11 Medical And Health Sciences Lipid Lipids Cell biology Circadian Rhythm Amino Acid Protein catabolism Circadian Oscillators medicine.anatomical_structure Neuroscience (all) Biochemistry Genetics and Molecular Biology (all) Immunology and Microbiology (all) Agricultural and Biological Sciences (all) ARNTL Transcription Factor Muscle Anatomy General Agricultural and Biological Sciences Human Muscle Protein Synthesis endocrine system Biosynthetic Techniques QH301-705.5 Knockout Biology Research and Analysis Methods General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Circadian Clocks Homeostasi medicine Genetics Animals Humans CLOCK Protein RNA Messenger Muscle Skeletal General Immunology and Microbiology Animal Protein turnover Skeletal muscle Correction Biology and Life Sciences Proteins Lipid metabolism Metabolism 06 Biological Sciences Lipid Metabolism Amino Acid Metabolism 030104 developmental biology chemistry Skeletal Muscles RNA 07 Agricultural And Veterinary Sciences Chronobiology 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Biology PLoS Biology, Vol 16, Iss 8, p e2005886 (2018) PLoS Biol. 16:e2005886 (2018) |
| Popis: | Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations. Author summary Circadian clocks are known to regulate local and systemic homeostasis by anticipating rhythmic changes in behavior and nutritional state and by compartmentalizing incompatible metabolic pathways within precise temporal and spatial windows. Yet a precise mechanistic understanding of how the circadian clock in skeletal muscle controls homeostasis is just beginning to come to light. Here, we investigated how the muscle clock directs 24-hr metabolic rhythms. We compared genome-wide binding of clock transcription factors brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα with 24-hr transcriptional and metabolic effects after their loss of function specifically in muscles. We found that the muscle clock plays a major role anticipating the transition from fasting to feeding. This occurs by direct activation of transcriptional programs promoting lipid storage, insulin sensitivity, and glucose metabolism, with coordinated repression of programs controlling lipid oxidation and protein catabolism. Importantly, these gene expression changes occur in the hours prior to systemic metabolic and hormonal cues that arise upon awakening. As such, we find that the muscle clock tips the scales in favor of glucose metabolism, whereas loss of function of the clock transcription factor BMAL1 is associated with persistent lipid metabolism, protein catabolism, and metabolic inefficiency. |
| Databáze: | OpenAIRE |
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