TY - JOUR

T1 - Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock

AU - Dyar, Kenneth Allen

AU - Hubert, Michaël Jean

AU - Mir, Ashfaq Ali

AU - Ciciliot, Stefano

AU - Lutter, Dominik

AU - Greulich, Franziska

AU - Quagliarini, Fabiana

AU - Kleinert, Maximilian

AU - Fischer, Katrin

AU - Eichmann, Thomas Oliver

AU - Wright, Lauren Emily

AU - Peña Paz, Marcia Ivonne

AU - Casarin, Alberto

AU - Pertegato, Vanessa

AU - Romanello, Vanina

AU - Albiero, Mattia

AU - Mazzucco, Sara

AU - Rizzuto, Rosario

AU - Salviati, Leonardo

AU - Biolo, Gianni

AU - Blaauw, Bert

AU - Schiaffino, Stefano

AU - Uhlenhaut, N Henriette

N1 - (Ekstern)

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052755602&partnerID=8YFLogxK

U2 - 10.1371/journal.pbio.2005886

DO - 10.1371/journal.pbio.2005886

M3 - Journal article

C2 - 30096135

AN - SCOPUS:85052755602

VL - 16

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 8

M1 - e2005886

ER -