The Peripheral Circadian Clock and Exercise: Lessons from Young and Old Mice.

Danielle R Bruns,Carly J Green,Musharraf Yusifova,Nicholas A Marcello,Whitney J Walker,Emily E Schmitt

doi:10.5334/jcr.201

Abstract

Critical biological processes are under control of the circadian clock. Disruption of this clock, e.g. during aging, results in increased risk for development of chronic disease. Exercise is a protective intervention that elicits changes in both age and circadian pathologies, yet its role in regulating circadian gene expression in peripheral tissues is unknown. We hypothesized that voluntary wheel running would restore disrupted circadian rhythm in aged mice. We analyzed wheel running patterns and expression of circadian regulators in male and female C57Bl/6J mice in adult (~4 months) and old (~18 months) ages. As expected, young female mice ran further than male mice, and old mice ran significantly less than young mice. Older mice of both sexes had a delayed start time in activity which likely points to a disrupted diurnal running pattern and circadian disruption. Voluntary wheel running rescued some circadian dysfunction in older females. This effect was not present in older males, and whether this was due to low wheel running distance or circadian output is not clear and warrants a future study. Overall, we show that voluntary wheel running can rescue some circadian dysfunction in older female but not male mice; and these changes are tissue dependent. While voluntary running was not sufficient to fully rescue age-related changes in circadian rhythm, ongoing studies will determine if forced exercise (e.g. treadmill) and/or chrono-timed exercise can improve age-related cardiovascular, skeletal muscle, and circadian dysfunction.

Highlights

The mammalian circadian clock governs physiological, endocrine, and metabolic responses coordinated in a 24-hour rhythmic pattern
Diurnal Circadian Wheel Running Activity Following wheel acclimation, hourly data was recorded for four days to determine circadian rhythm of wheel running activity
Voluntary wheel running for two weeks can rescue age related decline in circadian rhythm in female but not male mice in a tissue-specific manner

Summary

Introduction

The mammalian circadian clock governs physiological, endocrine, and metabolic responses coordinated in a 24-hour rhythmic pattern. The suprachiasmatic nucleus (SCN), located in the hypothalamus, is a group of neurons that each contain a molecular clock and together acts as the overall pacemaker to multiple circadian oscillators including those in peripheral tissues where key circadian rhythm genes are expressed [1]. The molecular clock operates on a positive and negative feedback loop system regulated by a number of genes. These genes include CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (Brain and Muscle ARNT (Aryl hydrocarbon receptor nuclear translocator-like protein-Like1) which are the activator genes that regulate a number of accessory genes in the molecular clock pathway. The accessory genes include Period (PER1), Period (PER2), Period (PER3), Crytochrome (CRY1), and Cryptochromes 2 (CRY2) which feedback to suppress the BMAL/CLOCK heterodimer [2]. PER2 is arguably the most important of the Period family of genes because PER2

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