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Dyar, Kenneth Allen; Hubert, Michael Jean; Mir, Ashfaq Ali; Ciciliot, Stefano; Lutter, Dominik; Greulich, Franziska; Quagliarini, Fabiana; Kleinert, Maximilian; Fischer, Katrin; Eichmann, Thomas Oliver; Wright, Lauren Emily; Paz, Marcia Ivonne Pena; Casarin, Alberto; Pertegato, Vanessa; Romanello, Vanina; Albiero, Mattia; Mazzucco, Sara; Rizzuto, Rosario; Salviati, Leonardo; Biolo, Gianni; Blaauw, Bert; Schiaffino, Stefano; Uhlenhaut, N. Henriette (2018): Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock.
In: PLOS Biology 16(8), e2005886
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Abstract

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-ERB alpha in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERB alpha, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERB alpha 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-ERB alpha-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-ERB alpha is related to temporal changes in gene expression and metabolite fluctuations.