Robert S. Bowen

Physical inactivity is associated with elevated risks for many chronic diseases and premature death. Both rodent and human studies indicate that sex steroids—testosterone and estrogen—play a role in the biological regulation of physical activity. The sex steroids likely affect brain physiology and/or the cellular condition of the skeletal muscle of the hind limb muscles used to complete a wheel running task. Differences in speed patterns between physiologically different sex steroid levels may indicate a deficiency in the skeletal muscle's capability to effectively contract during wheel running, while differences in the accumulated duration pattern during wheel running may indicate a deficiency in central motivation to complete a prolonged wheel running bout. The purpose of this study was to assess wheel running speed and duration patterns in male C57BL/6J mice under normal and physiologically‐deficient testosterone conditions. Wheel running data were collected for ten days (n=14 physiologically normal; n=12 testosterone deficient) and each wheel revolution was counted and time‐stamped to accumulate a daily turn‐by‐turn wheel revolution record. Testosterone deficiency was induced via bilateral orchidectomy ten‐days prior to wheel running assessment. Ten‐day average speed (m·min ⁻¹ ) and accumulated duration (% of total activity during the dark period) were assessed in four 3‐hour epochs during the dark period (epoch 1: 6pm–9pm, epoch 2: 9pm–12am, epoch 3: 12am–3am, epoch 4: 3am–6am). Differences in speed and duration data across epochs and between treatment groups were compared by separate 4 × 2 mixed‐design ANOVAs. Wheel running speed was significantly [ F (3,72)=6.5, p =0.001] different across epochs and between treatments. Wheel running speed remained consistent across all epochs in intact mice but decreased from a zenith during the initial epoch (mean±sd: 30.1±5.0 m·min ⁻¹ ) to a nadir (26.9±3.8 m·min ⁻¹ ) in deficient animals during the latter epochs. Intact mice ran faster (31.4±2.8 m·min ⁻¹ ) than deficient mice (26.1±5.4 m·min ⁻¹ ) throughout the dark period as a whole. Wheel running duration was significantly [ F (3,72)=28.8, p Support or Funding Information This project was supported by the Pilgram Marpeck School of STEM intramural research fund at Truett McConnell University. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The biological mechanisms regulating physical activity patterns appear to be linked to the sex hormones. Elucidation of these regulatory mechanisms may enhance individual physical activity patterns producing positive gains in health. Purpose: The purpose of this study was to evaluate the prolonged effects of estrogen on wheel running distance, duration, and speed in orchidectomized mice. Methods: The physical activity patterns of 9-wk-old C57BL/6j male mice (n = 28) were observed. Wheel running distance, duration, and speed were assessed under physiological conditions for 7 d. Next, physical activity patterns were evaluated after bilateral orchidectomy (n = 14) or sham orchidectomy (n = 14) for an additional 7 d. Orchidectomized mice were provided estrogen containing capsules for three additional weeks; control mice were provided estrogen-free capsules. Wheel running distance, duration, and speed were analyzed by three two-way (treatment group–phase of study) analysis of variance tests. Results: Wheel running speed was unaffected by sex hormone status. Distance (mean ± SD = 6.74 ± 2.13 km at baseline) decreased significantly after orchidectomy (2.27 ± 1.55 km) and remained low after initial estrogen treatment (3.04 ± 1.05 km). Prolonged estrogen exposure sustained a significant elevation of daily distance (4.47 ± 1.87 km). Prolonged estrogen exposure recovered and significantly sustained wheel running duration (baseline, 248 ± 60 min; postorchidectomy, 102 ± 53 min; prolonged exposure, 170 ± 63 min). Conclusions: Wheel running behavior was reduced significantly after orchidectomy and remained low after initial treatment with estrogens, but recovered to near control levels after 2 wk of exposure to estrogens. The estrogenic mechanism regulating wheel running behavior in male mice appears to induce an extensive but slow acting biological mechanism. Understanding the biological drive behind this mechanism may aid in developing useful therapeutic strategies to combat health issues related to physical inactivity.

Physical inactivity is a leading cause of hypokinetic diseases – obesity, heart disease, diabetes, and certain types of cancers. Increased city walkability, better access to fitness facilities, and remediation of socioeconomic barriers prove successful for limited populations within the confines of stringently controlled environments; however, these strategies fail to reverse the ever‐increasing physical inactivity epidemic on a global scale indicating the existence of other unidentified factors. These purported biological factors remain critical targets to understand the regulation of this complex phenotype. An estrogenic mechanism that incompletely or slowly adjusts physical activity levels following reintroduction of estrogenic compounds to surgically gonadectomized mice has been postulated to exist. Currently, this mechanism remains scrutinized due to concerns that elevated estrogen levels induce urinary bladder distension. The distension of the urinary bladder may mechanically disrupt physical activity, masking any physiological effects estrogen has on physical activity. The purpose of this study was to evaluate the effects of estrogen on physical activity levels while employing dose‐related strategies to alleviate distension in mice. Wheel running data were collected under normal physiological conditions, following removal of endogenous sex steroids via orchidectomy, and during estrogen replacement at various doses (0%, 10%, 50% or 100% estrogen‐containing implants) to induce varying degrees of urinary bladder distension. Wheel running distance (P = 0.005) and duration (P = 0.006) decreased after orchidectomy, but slowly increased following estrogen replacement. During the study, wheel running did not return to the levels observed in physiologically intact mice. Significant distension was not observed between estrogen treatment groups indicating that a slow‐responding estrogen effect exists in male mice that prevents wheel running from returning to normal levels immediately following steroid reintroduction. The limited increase in wheel running during estrogen treatment following orchidectomy is not an artifact of induced urinary bladder distension.

The genetic factors involved in the regulation of physical activity are not well understood. The dopamine system has been implicated in the control of voluntary locomotion and wheel running (WR) in mice and is thus a likely candidate as a genetic/biological system important to the regulation of physical activity. This study evaluated the effects of four different dopaminergic acting drugs on WR in differentially active inbred strains of mice. High active C57L/J (n=7, 3 controls, 4 experimental) and low active C3H/HeJ (n=8, 3 controls, 5 experimental) were analyzed for baseline wheel-running indices of distance (km/day), duration (mins/day), and speed (m/min) for 21 days. Experimental mice received increasing doses over four days of each of the following drugs: SKF 81297 (D1 agonist), SCH 23390 (D1 antagonist), GBR 12783 (DAT inhibitor), and AMPT (tyrosine hydroxylase inhibitor). Each drug dose response treatment was separated by three days of recovery (no drug injections). WR indices were monitored during drug treatments and during drug wash-out phases. SKF 81297 significantly reduced (p=0.0004) WR in the C57L/J mice, but did not affect WR in the C3H/HeJ mice. GBR 12783 significantly increased (p=0.0005) WR in C3H/HeJ mice, but did not affect WR in C57L/J mice. Only duration (not overall WR) was significantly reduced in C57L/J mice in response to SCH 23390 (p=0.003) and AMPT (p=0.043). SCH 23390 (p=0.44) and AMPT (p=0.98) did not significantly affect WR in C3H/HeJ mice. These results suggest that genetic differences in dopamine signaling may play a role in the WR response to dopaminergic-acting drugs in inbred strains of mice. The high activity in the C57L/J strain appears most responsive to D1-like receptor acting drugs, while in the C3H/HeJ strain, dopamine re-uptake appears to have an influence on activity level.

There is limited information regarding the physiological and psychological demands of the racing environment, and the subsequent effect on the performance of pit crew athletes. The purpose of this study was to evaluate heart rates (HRs) and core body temperatures (CTs) of pit crew athletes in the race environment. The HR and CT of pit crew athletes (n = 7) and control subjects were measured during 6 National Association for Stock Car Automobile Racing Sprint Cup races using ingestible sensors (HQ Inc, Palmetto, FL, USA). The HR and CT were measured before each race, at 15-minute intervals during the race, and upon completion of each pit stop. Compared to the control subject at each race, the pit crew athletes had significantly (p = 0.014) lower core temperatures (CTs). The pit crew athletes displayed higher HRs on the asphalt tracks than on concrete tracks (p = 0.011), and HR responses of the crew members were significantly (p = 0.012) different between pit crew positions, with the tire changers and jackman exhibiting higher HRs than the tire carriers. Unexpectedly, the CTs of the pit crew athletes were not elevated in the race environment, despite high ambient temperatures and the extensive fire-protection equipment (e.g., helmet, suit, gloves) each pit crew athlete wore. The lack of CT change is possibly the result of the increased HR more efficiently shunting blood to the skin and dissipating heat as a consequence of the athletes' extensive training regimen and ensuing heat acclimation. Additionally, it is possible that psychological stress unique to several of the tracks provided an additive effect resulting in increased heart rates.

The relationship between physical activity levels and disease rates has become an important health-related concern in the developed world. Heart disease, certain cancers and obesity persist at epidemic rates in the US and Western Europe. Increased physical activity levels have been shown to reduce the occurrence of many chronic diseases leading to reductions in the burden on the healthcare system. Activity levels in humans are affected by many cultural and environmental factors; nevertheless, current research points to a strong biological input with potential genetic, neurological and endocrinological origins. Of unique interest, the sex hormones appear to have a very strong influence on activity levels. The current animal literature suggests that females tend to be more active than males due to biological pathways of estrogenic origin. The majority of human epidemiological and anthropological data, on the contrary, suggest women are less active than men in spite of this inherent activity-increasing mechanism. The purpose of this study is to review the current literature regarding the control of physical activity levels by the sex hormones in humans. Using the natural transitional phases of the aging endocrine system, natural periodicity of the menstrual cycle and pharmacological/hormone replacement therapy as variable experimental stages, some authors have been able to provide some information regarding the existence of an inherent activity-increasing mechanism in humans. In brief, activity levels during life stages prior to and after menopause do not significantly differ, despite the vast changes in sex hormone levels and function. Sex hormone differences throughout a regular menstrual cycle do not appear to influence activity levels in humans either; an effect that is pronounced in the female rodent. The use of hormone replacement therapies provides researchers with more systematic controls over hormone modulation in human subjects; however, this benefit comes with additional confounding variables, mostly due to disease or other states of malfunction. Despite the addition of these confounding factors, minor changes to the activity pattern have been observed in women, especially during the initial administration of the therapy. Observations are yet to be made in male subjects during replacement therapy. In general, some evidence exists suggesting that a biological mechanism extending from the sex hormones influences activity in humans. Unfortunately, despite a small number of investigative reports, the paucity of human research investigating how the sex hormones affect activity levels in humans prevents conclusive delineation of the mechanisms involved. Future research in this unique sub-field of endocrinology and exercise science utilizing more appropriate research protocols and effective techniques will provide definitive evidence of such mechanisms.

Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (≈8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity.