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. An ex vivo measure of insulin sensitivity in skeletal muscle was determined from radioassays. RER was lower for muscle overexpressed females compared to WT females. 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 males, but not WT males. 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.

The exercise sex gap and the impact of the estrous cycle on exercise performance in mice

“…The antiandrogen Flutamide decreases the treadmill endurance of rats, but does not change O 2max and running economy 26 . Here, the exercise-induced submaximal O 2 and CO 2 up to O 2max were similar between sexes, as previously described 11 , 12 , 27 . Only one study demonstrated increased female submaximal O 2 during treadmill test, which further reinforces the hypothesis of females’ worst running economy 27 .…”

“…The minor representation of females also translates into less knowledge about the biology of exercise in this sex. So far, the main features of sexual dimorphism important for exercise described in rodents are differences in skeletal muscle kinetics and fiber-type composition 10 and energy metabolism 11 , 12 . In fact, the biological mechanisms underlying the benefits of exercise were investigated in numerous animal studies in a laboratory setting, with a strong tendency to only use males probably to avoid dealing with the possible influence of the menstrual/estrous cycle 9 , 13 .…”

Bmal1 function in skeletal muscle regulates sleep

“…Furthermore, whole body deletions of other circadian factors such as Per1 and Per2 ( Shiromani et al, 2004 ), and Cry1 and Cry2 ( Wisor et al, 2008 ), do not have similar effects on sleep. Other potential contributors could be related to changes in muscle metabolism as Bmal1 metabolic phenotypes have been reported in both muscle mouse-lines used here ( Harfmann et al, 2016 ; Brager et al, 2017 ).…”

“…Thus, these results suggest an important role for skeletal muscle in sleep regulation, implying that Bmal1 -dependent processes in skeletal muscle may be useful therapeutic targets for sleep disorders. In an effort to investigate the therapeutic potential of muscle Bmal1 , we examined sleep architecture in wild type mice harboring either the brain or muscle-specific ( Brager et al, 2017 ) Bmal1 transgene. In these mice, transgene expression is in addition to endogenous Bmal1 expression.…”

Ad libitum Weekend Recovery Sleep Fails to Prevent Metabolic Dysregulation during a Repeating Pattern of Insufficient Sleep and Weekend Recovery Sleep

“…In addition to weight gain, altered circadian timing in skeletal muscle could contribute to reduced muscle insulin sensitivity. For example, overexpression of the core clock gene, brain and muscle-ARNT-like factor (BMAL1) in skeletal muscle results in decreased insulin-stimulated skeletal-muscle glucose uptake during acute sleep loss in mice [64]. These findings suggest that disruption of the skeletal-muscle circadian clocks can contribute to decreased skeletal-muscle insulin sensitivity during sleep loss.…”