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It is clear, based on a deep scientific literature base, that genetic and genomic factors play significant roles in determining a wide range of sport and exercise characteristics including exercise endurance capacity, strength, daily physical activity levels, and trainability of both endurance and strength. Although the research field of exercise systems genetics has rapidly expanded over the past two decades, many researchers publishing in this field are not extensively trained in molecular biology or genomics techniques, sometimes creating gaps in generating high-quality and cutting-edge research for publication. As current or former Associate Editors for Medicine and Science in Sports and Exercise that have handled the majority of exercise genetics articles for Medicine and Science in Sports and Exercise in the past 15 yr, we have observed a large number of scientific manuscripts submitted for publication review that have exhibited significant flaws preventing their publication; flaws that often directly stem from a lack of knowledge regarding the "state-of-the-art" methods and accepted literature base that is rapidly changing as the field evolves. The purpose of this commentary is to provide researchers—especially those coming from a nongenetics background attempting to publish in the exercise system genetics area—with recommendations regarding best-practice research standards and data analysis in the field of exercise systems genetics, to strengthen the overall literature in this important and evolving field of research. [ABSTRACT FROM AUTHOR]

Introduction: Auto racing poses a unique set of physiologic challenges for athletes who compete in this sport. These challenges are not widely recognized due to the limited amount of original research in this field and the diffuse nature of this literature. The purpose of this article is to review the major physiologic challenges of auto racing and summarize what is currently known about athletes in this sport. Conclusions: The physical stressors of either driving or servicing the race car are overlaid with particular environmental challenges associated with racing (e.g., thermal, noise, carbon monoxide exposure) that increase the physiological stress on motorsport athletes. Physical stress reflects the muscular work required for car control and control of posture during high gravitational (g) loads: factors that predispose athletes to fatigue. The physiologic effects of these stressors include cardiovascular stress as reflected by prolonged elevation of heart rate, cardiac output, and oxygen consumption in both driver and pit athletes during competition. Psychological stress is evident in autonomic and endocrine responses of athletes during competition. The thermal stress of having to compete wearing multilayer fire suits and closed helmets in ambient temperatures of 50°C to 60°C results in the ubiquitous risk of dehydration. Published data show that both drivers and pit crew members are accomplished athletes with distinct challenges and abilities. There are gaps in the literature, especially in regard to female, older adult, and child participants. Additionally, minimal literature is available on appropriate training programs to offset the physiological challenges of auto racing. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and non-human animal models. This consensus paper, developed as a result of an ACSM-sponsored round table, provides a brief review of the theoretical concepts and existing literature that supports a significant role of genetic and other biological factors in the regulation of physical activity. Conclusion: Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants. [ABSTRACT FROM AUTHOR]

The literature strongly suggests that daily physical activity is genetically and biologically regulated. Potential identities of the responsible mechanisms are unclear, but little has been written concerning the possible evolutionary selection pressures leading to the development of genetic/biological controls of physical activity. Given the weak relationship between exercise endurance and activity levels and the differential genomic locations associated with the regulation of endurance and activity, it is probable that regulation of endurance and activity evolved separately. This hypothesis paper considers energy expenditures and duration of activity in hunter/gatherers, pretechnology farmers, and modern Western societies and considers the potential of each to selectively influence the development of activity regulation. Food availability is also considered given the known linkage of caloric restriction on physical activity as well as early data relating food oversupply to physical inactivity. Elucidating the selection pressures responsible for the genetic/biological control of activity will allow further consideration of these pressures on activity in today's society, especially the linkages between food and activity. Further, current food abundance is removing the cues for activity that were present for the first 40,000 years of human evolution, and thus future research should investigate the effects of this abundance upon the mechanisms regulating activity. [ABSTRACT FROM AUTHOR]

Although it is well known that physical activity prevents and ameliorates a large number of conditions and chronic diseases, it is also incontrovertible that physical inactivity is becoming more prevalent. This paradox has led some to suggest that genetic/biological factors influence activity levels as opposed to the classical notion that voluntary activity is solely regulated by environmental factors. There is a plethora of recent data showing that there is considerable genetic influence on activity levels in both humans and animals and emerging evidence suggesting potential genomic locations for those genetic factors. Several independent lines of evidence suggest that dopamine receptor 1 (Drd1) and nescient helix loop helix (Nh/h2) are excellent candidate genes for the regulation of physical activity, with several other potential candidate genes only partially supported. This foundation provides the basis for continuing work to identify additional candidategenes, to identify other genetic factors that are involved in the regulation of physical activity, and to investigate the mechanisms by which these genes and genetic factors regulate activity. [ABSTRACT FROM AUTHOR]

The genomic locations and identities of the genes that regulate voluntary physical activity are presently unknown. The purpose of this study was to search for quantitative trait loci (QTL) that are linked with daily mouse running wheel distance, duration, and speed of exercise. F2 animals (n 310) derived from high active C57L/J and low active C3H/HeJ inbred strains were phenotyped for 21 days. After phenotyping, genotyping with a fully informative single-nucleotide polymorphism panel with an average intermarker interval of 13.7 cM was used. On all three activity indexes, sex and strain were significant factors, with the F2 animals similar to the high active C57L/J mice in both daily exercise distance and duration of exercise. In the F2 cohort, female mice ran significantly farther, longer, and faster than male mice. QTL analysis revealed no sex-specific QTL but at the 5% experimentwise significance level did identify one QTL for duration, one QTL for distance, and two QTL for speed. The QTL for duration (DUR13.1) and distance (DIST13.1) colocalized with the QTL for speed (SPD13.1). Each of these QTL accounted for 6% of the phenotypic variance, whereas SPD9.1 (chromosome 9, 7 cM) accounted for 11.3% of the phenotypic variation. DUR13.1, DIST13.1, SPD13.1, and SPD9.1 were subsequently replicated by haplotype association mapping. The results of this study suggest a genetic basis of voluntary activity in mice and provide a foundation for future candidate gene studies. [ABSTRACT FROM AUTHOR]

The contribution to the regulation of forearm blood flow (FBF) by different baroreceptor populations has previously only been studied over a limited range of stimuli. Therefore, FBF and R-R interval were recorded during neck suctions and neck pressures ranging from -60 to +40 mmHg. The change in R-R interval (?R-R) during neck suction was significantly increased at each stage when compared to the control (P<0.05). ?R-R did not show any significant change during any of the neck pressure stages (P>0.05). Suction or pressure applied to the neck did not elicit any significant changes in FBF when compared to the control (P>0.05). These data show that widening the range of applied stimuli to carotid sinus baroreceptors does not induce a change in FBF. However, the small transient changes reported previously cannot be discounted. [ABSTRACT FROM AUTHOR]

Breathing carbon dioxide (CO2) is known to induce hypercapnic acidosis and to affect chemoreceptor regulation of the cardiovascular system. However, there is limited information in the literature regarding the effects of breathing CO2 upon tolerance to orthostatic stress where cardiovascular regulation is challenged. The purpose of this study was to investigate the effect of breathing 5% CO2 on presyncopal tolerance to lower body negative pressure (LBNP). Nine subjects (five males and four females; average ± S.D. age 21.9 ± 0.9 years, height 172.4 ± 9.7cm, mass 70.3 ± 7.1 kg) volunteered to participate in this study. Orthostatic tolerance was determined by exposing subjects to LBNP until the onset of presyncopal signs and symptoms on two occasions each separated by approximately 1 week. On one occasion investigations were carried out while subjects were breathing room air and on the other while subjects were breathing air containing 5% CO2, inducing hypercapnia and stimulating systemic chemoreceptors. During hypercapnic conditions, as compared with normocapnia, there were significant increases (P < 0.05) in minute ventilation, end-tidal CO2 and estimated arterial PCO2. Furthermore, under hypercapnic conditions there was an increase in orthostatic tolerance, peak heart rate and time to peak heart rate during LBNP. The LBNP-induced increase in calf circumference was significantly attenuated at -50 mmHg of LBNP in addition to a further 22.3% reduction in stroke volume under hypercapnic conditions. In conclusion, these results suggest that the possible protective element of presyncope was delayed during hypercapnia at the expense of further reductions in stroke volume. This delayed presyncopal response may have been associated with increases in cerebral blood flow (CBF) induced by the increased arterial PCO2. [ABSTRACT FROM AUTHOR]

Provides information on a study investigating a method for teaching students the benefits of using the peer reviews system in the teaching of physiology. Methodology used to conduct the study; Details on the approach used; Findings of the study.

Presents information on the result of an experiment on the different peer review systems used in scientific publishing. Advantages and disadvantages of peer review; Method used in the experiment; Class ground rules enhancing the student's comfort with the exercise.

The article presents a commentary on physical activity and epigenetics. Topics discussed include mechanisms arising from environmental factors external to the cell that alter gene expression without altering the underlying DNA; play critical roles in the regulation of many physiological pathways; and regulating physical activity or were regulated by physical activity.

The article discusses research being done on the use of McArdle's syndrome model in studying skeletal muscle metabolism dysfunction. It references the study "Muscle Signaling in Exercise Intolerance Insights from the McArdle Mouse Model," C. Fiuza-Luces et al. in the 2016 issue of "Medicine & Science in Sports & Exercise." The variables considered include muscle metabolism limitations and exercise intolerance, the effect of glycolysis on patients with McArdle's disease.

Purpose: Obesity is thought to negatively impact bone quality and strength despite improving bone mineral density. We hypothesized that 1) continuous consumption of a high-fat, high-sugar (HFS) diet would impair bone quality and strength, and 2) a change from an HFS diet to a low-fat, low-sugar (LFS) would reverse HFS-induced impairments to bone quality and strength. Methods: Six-week-old male C57Bl/6 mice (n = 10/group) with access to a running wheel were randomized to an LFS diet or anHFS diet with simulated sugar-sweetened beverages (20%fructose in place of regular drinkingwater) for 13wk.HFS mice were subsequently randomized to continuing HFS feeding (HFS/HFS) or transition to the LFS diet (HFS/LFS) for four additional weeks. Results: HFS/HFS mice exhibited superior femoral cancellous microarchitecture (i.e., greater BV/TV, Tb.N, Tb. Th, and decreased Tb. Sp) and cortical bone geometry (i.e., lower Ct.CSA and pMOI) compared with all other groups. At the femoral mid-diaphysis, structural, but notmaterial, mechanical properties were greatest in HFS/HFSmice. However, HFS/HFS exhibited greater femoral neck strength only when comparedwithmice assigned to diet transition (HFS/LFS). Osteoclast surface and the percentage of osteocytes staining positive for interferon-gamma were greater in HFS/LFS mice, consistent with reduced cancellous microarchitecture postdiet transition. Conclusions: HFS feeding enhanced bone anabolism and structural, but not material, mechanical properties in exercising mice. A change from an HFS to LFS diet returned the bone structure to that of continuously LFS-fed mice while compromising strength. Our results indicate rapid weight loss from obese states should be performed with caution to prevent bone fragility. A deeper analysis into the altered bone phenotype in diet-induced obesity from a metabolic standpoint is needed. [ABSTRACT FROM AUTHOR]

Exercise training which meets the recommendations set by the National Physical Activity Guidelines ensues a multitude of health benefits towards the prevention and treatment of various chronic diseases. However, not all individuals respond well to exercise training. That is, some individuals have no response, while others respond poorly. Genetic background is known to contribute to the inter-individual (human) and -strain (e.g., mice, rats) variation with acute exercise and exercise training, though to date, no specific genetic factors have been identified that explain the differential responses to exercise. In this review, we provide an overview of studies in human and animal models that have shown a significant contribution of genetics in acute exercise and exercise training-induced adaptations with standardized endurance and resistance training regimens, and further describe the genetic approaches which have been used to demonstrate such responses. Finally, our current understanding of the role of genetics and exercise is limited primarily to the nuclear genome, while only a limited focus has been given to a potential role of the mitochondrial genome and its interactions with the nuclear genome to predict the exercise training-induced phenotype(s) responses. We therefore discuss the mitochondrial genome and literature that suggests it may play a significant role, particularly through interactions with the nuclear genome, in the inherent ability to respond to exercise. [ABSTRACT FROM AUTHOR]

The literature strongly suggests that daily physical activity is genetically and biologically regulated. Potential identities of the responsible mechanisms are unclear, but little has been written concerning the possible evolutionary selection pressures leading to the development of genetic/biological controls of physical activity. Given the weak relationship between exercise endurance and activity levels and the differential genomic locations associated with the regulation of endurance and activity, it is probable that regulation of endurance and activity evolved separately. This hypothesis paper considers energy expenditures and duration of activity in hunter/gatherers, pretechnology farmers, and modern Western societies and considers the potential of each to selectively influence the development of activity regulation. Food availability is also considered given the known linkage of caloric restriction on physical activity as well as early data relating food oversupply to physical inactivity. Elucidating the selection pressures responsible for the genetic/biological control of activity will allow further consideration of these pressures on activity in today's society, especially the linkages between food and activity. Further, current food abundance is removing the cues for activity that were present for the first 40,000 years of human evolution, and thus future research should investigate the effects of this abundance upon the mechanisms regulating activity. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Purpose: Chronic overfeeding via a high-fat/high-sugar (HFHS) diet decreases wheel running and substantially alters the gut metabolome of C57BL/6J mice. In this study, we tested the hypothesis that fecal microbial transplants can modulate the effect of diet on wheel running. Methods: Singly housed, 6-wk-old male C57BL/6J mice were fed either a grain-based diet (CHOW) or HFHS diet and provided a running wheel for 13 wk. Low-active, HFHS-exposed mice were then either switched to a CHOW diet and given an oral fecal microbial transplant from mice fed the CHOW diet, switched to a CHOW diet and given a sham transplant, or remained on the HFHS diet and given a fecal microbial transplant from mice fed the CHOW diet. Total wheel running, nutrient intake, body composition, fecal microbial composition, fecal metabolite composition, and liver steatosis were measured at various times throughout the study. Results: We found that an HFHS diet decreases wheel running activity, increases body fat, and decreases microbial alpha diversity compared with a CHOW diet. Improvements in wheel running, body composition, and microbial alpha diversity were accomplished within 2 wk for mice switched from an HFHS diet to a CHOW diet with no clear evidence of an added benefit from fecal transplants. A fecal transplant from mice fed a CHOW diet without altering diet did not improve wheel running or body composition. Wheel running, body composition, fecal microbial composition, fecal metabolite composition, and liver steatosis percentage were primarily determined by diet. Conclusions: Our results suggest that diet is a primary mediator of wheel running with no clear effect from fecal microbial transplants. [ABSTRACT FROM AUTHOR]

The article discusses research on the physical characteristics of National Association for Stock Car Auto Racing (NASCAR) Sprint Cup pit crew athletes. Topics explored include the significant responsibilities of the pit crew during the NASCAR race season, the evaluation of their performance in terms of agility, flexibility, and muscular endurance, and the use of the BodPod software for measuring and analyzing body composition of concerned pit crew athletes.

We estimated sibling resemblance in health-related physical fitness (PF) and examined how individual characteristics and shared natural environment accounted for sibling similarities. The sample comprised 656 sibling pairs and 102 triplets (6–15 years of age), from three geographical areas of Peru. PF components included morphological (waist circumference, sum of skinfolds), muscular (handgrip strength, standing long jump), and motor (shuttle-run). Body mass index (BMI) and somatic maturation were also assessed. In general, sibling intraclass correlations differed significantly across sib-ship types for waist circumference and handgrip strength but were the same for sum of skinfolds, standing long jump, and shuttle-run. Further, in general, both individual characteristics and geographical area of residence significantly influenced the magnitude of sibling resemblance as well as the mean levels of PF. In conclusion, individual characteristics and shared natural environment jointly influenced the expression of PF in Peruvian siblings, revealing the importance of these features when designing individualized programs promoting fitness. [ABSTRACT FROM AUTHOR]

Physical activity is associated with disease prevention and overall wellbeing. Additionally there has been evidence that physical activity level is a result of genetic influence. However, there has not been a reliable method to silence candidate genes in vivo to determine causal mechanisms of physical activity regulation. Vivo-morpholinos are a potential method to transiently silence specific genes. Thus, the aim of this study was to validate the use of Vivo-morpholinos in a mouse model for voluntary physical activity with several sub-objectives. We observed that Vivo-morpholinos achieved between 60–97% knockdown of Drd1-, Vmat2-, and Glut4-protein in skeletal muscle, the delivery moiety of Vivo-morpholinos (scramble) did not influence physical activity and that a cocktail of multiple Vivo-morpholinos can be given in a single treatment to achieve protein knockdown of two different targeted proteins in skeletal muscle simultaneously. Knocking down Drd1, Vmat2, or Glut4 protein in skeletal muscle did not affect physical activity. Vivo-morpholinos injected intravenously alone did not significantly knockdown Vmat2-protein expression in the brain (p = 0.28). However, the use of a bradykinin analog to increase blood-brain-barrier permeability in conjunction with the Vivo-morpholinos significantly (p = 0.0001) decreased Vmat2-protein in the brain with a corresponding later over-expression of Vmat2 coincident with a significant (p = 0.0016) increase in physical activity. We conclude that Vivo-morpholinos can be a valuable tool in determining causal gene-phenotype relationships in whole animal models. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F2 population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals. Results: This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations. Conclusions: It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed. [ABSTRACT FROM AUTHOR]

With the rise in physical inactivity and its related diseases, it is necessary to understand the mechanisms involved in physical activity regulation. Biological factors regulating physical activity are studied to establish a possible target for improving the physical activity level. However, little is known about the role metabolism plays in physical activity regulation. Therefore, we studied protein fractional synthesis rate (FSR) of multiple organ tissues of 12-week-old male mice that were previously established as inherently low-active (n = 15, C3H/HeJ strain) and high-active (n = 15, C57L/J strain). Total body water of each mouse was enriched to 5% deuterium oxide (D2O) via intraperitoneal injection and maintained with D2O enriched drinking water for about 24 h. Blood samples from the jugular vein and tissues (kidney, heart, lung, muscle, fat, jejunum, ileum, liver, brain, skin, and bone) were collected for enrichment analysis of alanine by LC-MS/MS. Protein FSR was calculated as -ln(1-enrichment). Data are mean±SE as fraction/day (unpaired t-test). Kidney protein FSR in the low-active mice was 7.82% higher than in high-active mice (low-active: 0.1863±0.0018, high-active: 0.1754±0.0028, p = 0.0030). No differences were found in any of the other measured organ tissues. However, all tissues resulted in a generally higher protein FSR in the low-activity mice compared to the high-activity mice (e.g. lung LA: 0.0711±0.0015, HA: 0.0643±0.0020, heart LA: 0.0649± 0.0013 HA: 0.0712±0.0073). Our observations suggest that high-active mice in most organ tissues are no more inherently equipped for metabolic adaptation than low-active mice, but there may be a connection between protein metabolism of kidney tissue and physical activity level. In addition, low-active mice have higher organ-specific baseline protein FSR possibly contributing to the inability to achieve higher physical activity levels. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Purpose: We designed the study to determine whether mitochondrial DNA (mtDNA) haplogroup, sequence, and heteroplasmy differed between individuals previously characterized as low (LR) or high responders (HR) as defined by their maximal oxygen uptake response to a standardized aerobic exercise training program. Methods: DNA was isolated from whole blood in subjects from the HERITAGE Family Study that were determined to be either HR (n = 15) or LR (n = 15). mtDNA was amplified by long-range polymerase chain reaction, then tagged with Nextera libraries and sequenced on a MiSeq instrument. Results: Different mtDNA haplogroup subtypes were found in HR and LR individuals. Compared with HR subjects, significantly more LR subjects had variants in 13 sites, including 7 in hypervariable (HV) regions: HV2 (G185A: 0 vs 6, P = 0.02; G228A: 0 vs 5, P = 0.04; C295T: 0 vs 6; P = 0.04), HV3 (C462T: 0 vs 5, P = 0.04; T489C: 0 vs 5; P = 0.04), and HV1 (C16068T: 0 vs 6, P = 0.02; T16125C: 0 vs 6, P = 0.02). Remaining variants were in protein coding genes, mtND1 (1 vs 8, P = 0.02), mtND3 (A10397G: 0 vs 5, P = 0.04), mtND4 (A11250G: 1 vs 8, P = 0.02), mtND5 (G13707A: 0 vs 5, P = 0.04), and mtCYTB (T14797C: 0 vs 5, P = 0.04; C15451A: 1 vs 8, P = 0.02). Average total numbers of heteroplasmies (P = 0.83) and frequency of heteroplasmies (P = 0.05) were similar between the groups. Conclusions: Our findings provide specific sites across the mitochondrial genome that may be related to maximal oxygen uptake trainability. [ABSTRACT FROM AUTHOR]

In this pilot work, we selected two inbred strains that respond well to endurance training (ET) (FVB/NJ, and SJL/J strains), and two strains that respond poorly (BALB/cByJ and NZW/LacJ), to determine the effect of a standardized ET treadmill program on mitochondrial and nuclear DNA (nucDNA) integrity, and mitochondrial DNA (mtDNA) copy number. DNA was isolated from plantaris muscles (n = 37) and a gene‐specific quantitative PCR‐based assay was used to measure DNA lesions and mtDNA copy number. Mean mtDNA lesions were not different within strains in the sedentary or exercise‐trained states. However, mtDNA lesions were significantly higher in trained low‐responding NZW/LacJ mice (0.24 ± 0.06 mtDNA lesions/10 Kb) compared to high‐responding strains (mtDNA lesions/10 Kb: FVB/NJ = 0.11 ± 0.01, p =.049; SJL/J = 0.04 ± 0.02; p =.003). ET did not alter mean mtDNA copy numbers for any strain, although both sedentary and trained FVB/NJ mice had significantly higher mtDNA copies (99,890 ± 4,884 mtDNA copies) compared to low‐responding strains (mtDNA copies: BALB/cByJ = 69,744 ± 4,675; NZW/LacJ = 65,687 ± 5,180; p <.001). ET did not change nucDNA lesions for any strain, however, SJL/J had the lowest mean nucDNA lesions (3.5 ± 0.14 nucDNA lesions/6.5 Kb) compared to all other strains (nucDNA lesions/6.5 Kb: FVB/NJ = 4.4 ± 0.11; BALB/cByJ = 4.7 ± 0.09; NZW/LacJ = 4.4 ± 0.11; p <.0001). Our results demonstrate strain differences in plantaris muscle mtDNA lesions in ET mice and, independent of condition, differences in mean mtDNA copy and nucDNA lesions between strains. [ABSTRACT FROM AUTHOR]

Our previous studies suggest that physical activity (PA) levels are potentially regulated by endogenous metabolic mechanisms such as the vasodilatory roles of nitric oxide (NO) production via the precursor arginine (ARG) and ARG-related pathways. We assessed ARG metabolism and its precursors [citrulline (CIT), glutamine (GLN), glutamate (GLU), ornithine (ORN), and phenylalanine (PHE)] by measuring plasma concentration, whole-body production (WBP), de novo ARG and NO production, and clearance rates in previously classified low-active (LA) or high-active (HA) mice. We assessed LA (n = 23) and HA (n = 20) male mice by administering a stable isotope tracer pulse via jugular catheterization. We measured plasma enrichments via liquid chromatography tandem mass spectrometry (LC-MS/MS) and body compostion by echo-MRI. WBP, clearance rates, and de novo ARG and NO were calculated. Compared to LA mice, HA mice had lower plasma concentrations of GLU (71.1%; 36.8 ± 2.9 vs. 17.5 ± 1.7μM; p<0.0001), CIT (21%; 57.3 ± 2.3 vs. 46.4 ± 1.5μM; p = 0.0003), and ORN (40.1%; 55.4 ± 7.3 vs. 36.9 ± 2.6μM; p = 0.0241), but no differences for GLN, PHE, and ARG. However, HA mice had higher estimated NO production ratio (0.64 ± 0.08; p = 0.0197), higher WBP for CIT (21.8%, 8.6 ± 0.2 vs. 10.7 ± 0.3 nmol/g-lbm/min; p<0.0001), ARG (21.4%, 35.0 ± 0.6 vs. 43.4 ± 0.7 nmol/g-lbm/min; p<0.0001), PHE (7.6%, 23.8 ± 0.5 vs. 25.6 ± 0.5 nmol/g-lbm/min; p<0.0100), and lower GLU (78.5%; 9.4 ± 1.1 vs. 4.1 ± 1.6 nmol/g lbm/min; p = 0.0161). We observed no significant differences in WBP for GLN, ORN, PHE, or de novo ARG. We concluded that HA mice have an activated whole-body ARG pathway, which may be associated with regulating PA levels via increased NO production. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the estimated mutation age and conservation of single-nucleotide polymorphisms (SNPs) associated with physical activity (PA) in humans. All human SNPs found to be significantly associated with PA levels in the literature were cross-referenced with the National Heart, Lung, and Blood Institute’s Grand Opportunity Exome Sequencing Project to find estimated African-American (AA) and European-American (EA) mutation age. As a secondary measure of mutation age, SNPs were searched for in Hawk’s mutation age prediction database which utilizes linkage equilibrium. To determine conservation among hominids, all SNPs were searched in the University of California, Santa Cruz Genome Browser, which contains Neanderthal and chimpanzee reference genomes. Six of the 104 SNPs associated with PA regulation were exon-located missense variants found in IFNAR2, PPARGC1A, PML, CTBP2, IL5RA, and APOE genes. The remaining 98 SNPs were located in non-protein coding regions. Average AA and EA estimated mutation age of the exon-located SNPs were 478.4 ± 327.5 kya and 542.1 ± 369.4 kya, respectively. There were four selective sweeps (suggestive of strong positive selection) of SNPs in humans when compared to Neanderthal or chimpanzee genomes. Exon-located PA candidate SNPs are older than the hypothesized emergence of anatomically modern humans. However, 95% of PA associated SNPs are found in intron and intergenic location. Across all SNPs, there seems to be a high level of conservation of alleles between humans, Neanderthals, and chimpanzees. However, the presence of four selective sweeps suggests there were selection pressures or drift unique to Homo sapiens that influenced the development of mutations associated with PA regulation. [ABSTRACT FROM AUTHOR]

Introduction: Voluntary physical activity levels are regulated by sex hormones. The purpose of this study was to determine the effect of the endocrine disruptor benzyl butyl phthalate (BBP) on the regulation of physical activity in mice. Methods: Mouse dams were treated with 500 mg⋅kg-1-d-1 of BBP or vehicle on gestation days 9-16. Pups were weaned and analyzed for voluntary physical activity levels, puberty development, sex hormone levels, and body composition during the 20-wk period. Results: Seventy-three offspring from BBP-treated dams were studied (n = 43 males and n = 30 females). Endocrine disruption was indicated by decreased anogenital distances in BBP-treated male offspring at 10 (P = 0.001) and 20 wk (P = 0.038) and delayed vaginal openings in BBP-treated female offspring (P = 0.001). Further, there was a significant decrease in serum testosterone concentration in male mice between control and BBP at 10 wk (P = 0.039) and at 20 wk (P = 0.022). In female mice, there was a significant increase in serum testosterone concentration in BBP mice at 20 wk (P = 0.002) and a significant increase in estrogen (estradiol) concentrations at 20 wk in the control female mice (P = 0.015). Overall, BBP mice ran significantly less distance (males, P = 0.008; females, P = 0.042) than controls. Other than a significant increase in BBP-treated males in fat mass at 20 wk (P = 0.040), there was no significant decrease in weight, lean mass, or fat mass in either female or male mice, regardless of treatment. Conclusion: Maternal endocrine disruption altered hormone response, but not body composition in either sex of offspring, with a corresponding decreased activity throughout early adulthood in all offspring. These results suggest that exposure to common environmental endocrine disruptors in utero can reduce and alter physical activity levels in offspring. [ABSTRACT FROM AUTHOR]

Physical inactivity is associated with the development of a variety of chronic illnesses. Literature has shown that physical activity is genetically regulated; however there is limited information on the mechanisms that influence this process with existing studies primarily focused on genomic and/or transcription association studies. There have been no studies to determine differential protein expression in the nucleus accumbens, the brain site thought to be involved in activity regulation, between high and low active animals. We compared the global nucleus accumbens proteome signature from known high- and low-active mice and identified seven differentially expressed proteins. Low active mice generally over expressed proteins associated with neural stress (Stress 70 protein and V type proton ATPase catalytic subunit A), and the high-active mice over expressed proteins associated with metabolism (creatine kinase B, succinyl-CoA ligase). Previously suggested mechanisms associated with activity regulation in the nucleus accumbens have centered on dopamine receptor 1 and endocannabinoid receptor 1. However, these proteins and the associated pathways were not differentially expressed between high and low active mice. In conclusion, protein expression must be determined as part of the effort to identify involved mechanisms in regulating activity and there appears to be separate nucleus accumbens proteome signatures associated with high- and low-active mice. [ABSTRACT FROM AUTHOR]

Studies on the determinants of physical activity have traditionally focused on social factors and environmental barriers, but recent research has shown the additional importance of biological factors, including genetic variation. Here we review the major tenets of this research to arrive at three major conclusions: First, individual differences in physical activity traits are significantly influenced by genetic factors, but genetic contribution varies strongly over age, with heritability of leisure time exercise behavior ranging from 27% to 84% and heritability of sedentary behaviors ranging from 9% to 48%. Second, candidate gene approaches based on animal or human QTLs or on biological relevance (e.g., dopaminergic or cannabinoid activity in the brain, or exercise performance influencing muscle physiology) have not yet yielded the necessary evidence to specify the genetic mechanisms underlying the heritability of physical activity traits. Third, there is significant genetic modulation of the beneficial effects of daily physical activity patterns on strength and endurance improvements and on health-related parameters like body mass index. Further increases in our understanding of the genetic determinants of sedentary and exercise behaviors as well as the genetic modulation of their effects on fitness and health will be key to meaningful future intervention on these behaviors. [ABSTRACT FROM PUBLISHER]

Reference 1 Cross KM, Granados JZ, Ten Have GAM, Thaden JJ, Engelen MPKJ, et al. (2020) Protein fractional synthesis rates within tissues of high- and low-active mice. The image for Fig 1 is incorrect. [Extracted from the article]

The article discusses the effect of innate activity level and running wheel access of food consumption in high-active and low-active mice. It states that the balance between food consumption and energy expenditure is important in maintaining the body mass. It also mentions that regardless of body mass, the increase in physical activity by using running wheels or treadmills resulted in the increased food consumption in rodents. Furthermore, it relates that there is a strong positive correlation between daily food intake and daily wheel activity, as measured by average daily distance, duration and speed. It also concluded that during the 13 weeks trial, the high-active and low-active mice tended to balance their energy intake with energy consumption.

Abstract: The biological regulating factors of physical activity in animals are not well understood. This study investigated differences in the central mRNA expression of seven dopamine genes (Drd1, Drd2, Drd3, Drd4, Drd5, TH, and DAT) between high active C57/LJ (n =17) male mice and low active C3H/HeJ (n =20) male mice, and between mice with access to a running wheel and without running wheel access within strain. Mice were housed with running wheels interfaced with a computer for 21 days with distance and duration recorded every 24h. On day 21, the striatum and nucleus accumbens were removed during the active period (∼9pm) for dopaminergic analysis. On average, the C57L/J mice with wheels ran significantly farther (10.25±1.37km/day vs. 0.01±0.09km/day, p <0.001), longer (329.73±30.52min/day vs. 7.81±6.32min/day, p <0.001), and faster (31.27±3.13m/min vs. 11.81±1.08m/min, p <0.001) than the C3H/HeJ mice with wheels over the 21 day period. No differences in gene expression were found between mice in either strain with wheels and those without wheels suggesting that access to running wheels did not alter dopaminergic expression. In contrast, relative expression for two dopamine genes was significantly lower in the C57L/J mice compared to the C3H/HeJ mice. These results indicate that decreased dopaminergic functioning is correlated with increased activity levels in C57L/J mice and suggests that D1-like receptors as well as tyrosine hydroxylase (an indicator of dopamine production), but not D2-like receptors may be associated with the regulation of physical activity in inbred mice. [Copyright &y& Elsevier]

Abstract: Purpose: Measurements of exercise behaviors in rodents such as maximal treadmill endurance and physical activity are often used in the literature; however, minimal data are available regarding the repeatability of measurements used for these exercise behaviors. This study assessed the repeatability of a commonly used maximal exercise endurance treadmill test as well as voluntary physical activity measured by wheel running in mice. Methods: Repeatability of treadmill tests were analyzed for both inbred and outbred mice in addition to a 10week repeatability analysis using Balb/cJ mice (n =20). Voluntary daily physical activity was assessed by distance, duration, and speed of wheel running (WR). Physical activity measurements on days 5 and 6 of WR in a large cohort (n =739) of both inbred and outbred mice were compared. Results: No significant differences (p >0.05) in exercise endurance were found between different cohorts of Balb/cJ and DBA/2J mice indicating strains overall generally test the same; however, significant differences between tests were seen within BaD2F2 animals (p <0.001). Bland–Altman analysis revealed a lack of agreement between weekly endurance tests within mouse, and correlation analysis showed lack of consistent correlations between weekly endurance tests within mouse. No significant differences were found for WR measurements within mouse between days (p =0.99). High correlations between days within mouse for WR were found (r =0.74–0.85). Conclusions: High intra-mouse variability between repeated endurance tests suggests that treadmill testing in an enclosed chamber with shock grid for motivation to run in mice is not repeatable. Conversely, high correlation and agreement between days of wheel-running measurements suggest that voluntary activity (WR) is repeatable and stable within individual mice. [Copyright &y& Elsevier]

Purpose: It is currently unknown whether the age of wheel exposure influences running wheel activity in mice. The purpose of this study was to determine whether the age at which a running wheel was introduced affected running wheel activity for a subsequent 15-wk period. Methods: Twenty female C57B1/6J mice (age 7 wk) were assigned to one of four experimental groups. Group 1 received a running wheel at 7 wk of age. Thereafter, groups 2, 3, and 4 received running wheels at 10, 13, and 16 wk of age, respectively. Daily running wheel activity (duration, distance, and velocity) was recorded from the time of running wheel exposure until 30 wk of age. Results: A repeated-measures MANOVA found significant differences between groups for distance (P = 0.02), duration (P = 0.04), and velocity (P = 0.001) during the 15-wk concurrent running period (age 16-30 wk). Post hoc tests revealed significantly greater distance and duration in group 4 compared with group 2 and significantly greater velocity in group 4 compared with each of the other groups. Significant interactions were found between groups over time for distance (P = 0.01) and duration (P = 0.05). No significant difference between groups was observed for body weight over the 24-wk period (P> 0.05). Conclusion: Although differences were found between groups 2 and 4, these data suggest that the age at which physical activity is introduced has little influence on the subsequent level of physical activity in C57B1/6J mice. However, it appears that introduction of the running wheel at 16 wk of age results in greater within group variance, suggestive of a greater environmental influence on daily running wheel activity. [ABSTRACT FROM AUTHOR]

PURPOSE: Recently published work by our group identified mitochondrial DNA (mtDNA) variants and heteroplasmy that differ between individuals categorized by high and low aerobic capacity (VO2max) trainability, part of the HERITAGE Family Study Cohort. Our purpose in this investigation was to assess insertions and deletions (indels) in mitochondrial genomes in high (HR) and low responders (LR). METHODS: DNA was isolated from whole blood in HERITAGE Family Study healthy subjects (subjects classified by change in VO2max: HR: n=15; LR: n =15). mtDNA was amplified by long-range polymerase chain reaction, then tagged with Nextera libraries, and sequenced on a Miseq instrument. An indel was defined as an insertion or deletion with a frequency of at least 1% at a specific location. For this study, we compared indel sites and the frequency they occurred between HR and LRs. RESULTS: Among subjects, we identified 11 total sites where an indel occurred in at least one individual: mtHVR2 (C285CA: LR = 1 individual; HR = 0 individuals), mtHVR2 (A302AC: LR = 1 individual; HR = 0 individuals), mtHVR3 (G513GCA: LR = 1 individual; HR = 1 individual), mtHVR3 (GCA513G: LR = 3 individuals; HR = 1 individual), mtHVR3 (A567AC: LR = 0 individuals; HR = 1 individual), mtND4 (GA11031G: LR = 0 individuals; HR = 1 individual), mtND5 (CA12417C: LR = 11 individuals; HR = 8 individuals), mtHVR 1 (CA16179C: LR = 0 individuals; HR = 2 individuals), mtHVR1 (A16182AC: LR = 0 individuals; HR = 2 individuals), mtHVR1 (CT16188C: LR = 0 individuals; HR = 3 individuals), mtHVR 1(C16192CT: LR = 0 individual; HR = 1 individual). The average total frequency across the indels in LR was 41.32 % (± 43.55 %) and 31.59 % (± 33.29 %) in HRs. We identified three sites with indels that were present in HR but not LR: mtHVR1 (CA16179C; 21.5% ± 0.71% mean indel frequency), mtHVR1 (A16182AC; 13.4% ± 0.57% mean indel frequency), and mtHVR1 (CT16188C; 17.4% ± 21.45% mean indel frequency). CONCLUSIONS: We found three sites with indels in the HVR1 region of the mitochondrial genome in HR but not LR. While our sample size is small, our findings highlight an area of the mitochondrial genome that is responsible for mtDNA replication that presents indels in individuals classified by low trainability. Our on-going work is to increase the sample size and assess indel implications on VO2max trainability. [ABSTRACT FROM AUTHOR]