title: Homeostatic effects of exercise and sleep on metabolic processes in mice with an overexpressed skeletal muscle clock.
abstract: Brain and muscle-ARNT-like factor (Bmal1/BMAL1) is an essential transcriptional/translational factor of circadian clocks. Loss of function of Bmal1/BMAL1 is highly disruptive to physiological and behavioral processes. In light of these previous findings, we examined if transgenic overexpression of Bmal1/BMAL1 in skeletal muscle could alter metabolic processes. First, we characterized in vivo and ex vivo metabolic phenotypes of muscle overexpressed mice (male and female) compared to wild-type littermates (WT). Second, we examined in vivo and ex vivo metabolic processes in the presence of positive and negative homeostatic challenges: high-intensity treadmill running (positive) and acute sleep deprivation (negative). In vivo measures of metabolic processes included body composition, respiratory exchange ratio (RER; VCO2/VO2), energy expenditure, total activity counts, and food intake collected from small animal indirect calorimetry. Ex vivo measure of insulin sensitivity in skeletal muscle was determined from radioassays. RER was lower for muscle overexpressed females compared to female WTs. There were no genotype-dependent differences in metabolic phenotypes for males. With homeostatic challenges, muscle overexpressed mice had lower energy expenditure after high-intensity treadmill running. Acute sleep deprivation reduced insulin sensitivity in skeletal muscle in overexpressed male mice, but not male WTs. The present study contributes to a body of evidence showing pleiotropic, non-circadian, and homeostatic effects of altered Bmal1/BMAL1 expression on metabolic processes, demonstrating a critical need to further investigate the broad and complex actions of Bmal1/BMAL1 on physiology and behavior.
authors.affiliation: Behavioral Biology Branch, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA. Electronic address: allison.j.brager.ctr@mail.mil.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Brager
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Heemstra
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: Raman
authors.initials: R
authors.lastname: Bhambra
authors.affiliation: Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Ehlen
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, 32611, USA.
authors.forename: Karyn A
authors.initials: KA
authors.lastname: Esser
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
authors.forename: Ketema N
authors.initials: KN
authors.lastname: Paul
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Novak
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D005260:Female; D006706:Homeostasis / Q000502:physiology; D008297:Male; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D012890:Sleep / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse
keywords: Insulin sensitivity; Molecular circadian clock; Resting energy expenditure; Restricted sleep; Treadmill running; VO(2) max