FGF21 Mediates the Associations between Exercise, Ageing, and Glucose Regulation Introduction Ageing increases the prevalence of glucose intolerance, but exercise improves glucose homeostasis. The fibroblast growth factor 21 (FGF21)-adiponectin axis helps regulate glucose metabolism. However, the role of FGF21 in mediating glucose metabolism with ageing and exercise remains unknown. Purpose This study examined whether FGF21 responses to a glucose challenge are associated with habitual exercise, ageing and glucose regulation. Methods Eighty age- and sex-matched healthy individuals were assigned to young sedentary and active (≤36 years old, n=20 each group) and older sedentary and active (≥45 years old, n=20 each group) groups. Fasted and post-prandial blood glucose concentration and plasma concentration of insulin, FGF21 and adiponectin were determined during an oral glucose tolerance test (OGTT). Results During the OGTT, glucose concentrations were 9% higher (p=0.008) and FGF21 concentrations were 58% higher (p=0.014) in the older than the younger group, independent of activity status. Active participants had 40% lower insulin concentration and 53% lower FGF21 concentration than sedentary participants, independent of age (all p<0.001). Adiponectin concentration during the OGTT did not differ by age (p=0.448) or activity status (p=0.611). Within the younger group, post-prandial glucose, insulin and FGF21 concentrations during the OGTT were lower in active than in sedentary participants. In the older group, only post-prandial insulin and FGF21 concentrations were lower in active participants. Conclusions FGF21, but not adiponectin, response during the OGTT is higher in older than younger adults and lower in active than sedentary individuals. Exercise-associated reduction in OGTT glucose concentrations was observed in younger but not older adults. Corresponding author: Chin Leong LIM; Email: fabianlim@ntu.edu.sg; 11 Mandalay Road, Singapore 308232, Singapore This study is supported by the Ministry of Education Singapore Start-up Grant for Human and Metabolic disease (L0412270). David Stensel acknowledges support from the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The authors declare no conflict of interest. The results of the present study do not constitute endorsement by ACSM. We declare that the results of the study are presented clearly, honestly and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 29 August 2019 © 2019 American College of Sports Medicine

“Chemotherapy-periodized” Exercise to Accommodate for Cyclical Variation in Fatigue PURPOSE The purpose of this study was to provide a rationale for ‘chemotherapy-periodized’ exercise by characterizing cyclical variations in fatigue and exercise response across a chemotherapy cycle and comparing exercise adherence during chemotherapy between a prescription that is periodized according to chemotherapy cycle length and a standard linearly progressed prescription. METHODS Women with breast cancer who were prescribed taxane-based chemotherapy were randomly assigned to a supervised aerobic and resistance exercise program following a chemotherapy-periodized exercise prescription (n=12) or to usual care during chemotherapy (n=15). Fatigue and steady state exercise responses were assessed in both groups prior to the first taxane treatment and across the third treatment (i.e., 0-3 days prior and 3-5 days after the third treatment, and 0-3 days prior to the fourth treatment) to assess cyclical variations. Adherence to the chemotherapy-periodized exercise prescription was compared to adherence to a standard linear prescription from a prior study in a similar population (n=51). RESULTS Fatigue increased from baseline (marginal mean±standard error: 3.2±0.4) to prior to the third treatment (4.1±0.4, p=0.025), then peaked at 3-5 days after the third treatment (5.1±0.4, p=0.001), before recovering prior to the next treatment (4.3±0.5, p=0.021). The peak in fatigue at 3-5 days post-third treatment corresponded to a decrease in steady state exercise oxygen consumption (VO2) (p=0.013). Compared to a standard linear exercise prescription during chemotherapy, a chemotherapy-periodized exercise prescription resulted in higher attendance during the week after chemotherapy (57±30% vs 77±28%, p=0.04) and overall attendance (63+25% vs 78±23%, p=0.05). CONCLUSION Fatigue and exercise VO2 vary across a chemotherapy cycle. A chemotherapy-periodized exercise prescription that accommodates cyclical variations in fatigue may increase adherence to supervised exercise. The first two authors contributed equally. Corresponding author: Dr. Kristin Campbell, 212-2177 Wesbrook Mall, Vancouver, Canada V6T1Z3, Ph:(604)-827-4704; Fx:(604)-822-1870; E:Kristin.Campbell@ubc.ca AK was supported by a Doctoral Award from the Canadian Institutes of Health Research and a Four-year fellowship from the University of British Columbia. Conflict of interest: The authors have no conflicts of interest to disclose. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 30 August 2019 © 2019 American College of Sports Medicine

A Critical Evaluation of Current Methods for Exercise Prescription in Women and Men Common methods to prescribe exercise intensity are based on fixed-percentages of maximum rate of oxygen uptake (V[Combining Dot Above]O2max), peak work rate (WRpeak), maximal heart rate (HRmax). However, it is unknown how these methods compare to the current models to partition the exercise intensity spectrum. Purpose Thus, the aim of this study was to compare contemporary gold-standard approaches for exercise prescription based on fixed-percentages of maximum values to the well established but underutilized “domain” schema of exercise intensity. Methods One hundred individuals participated in the study (women=46; men=54). A cardiopulmonary ramp-incremental test was performed to assess V[Combining Dot Above]O2max, WRpeak, HRmax, and the lactate threshold (LT), and submaximal constant-work rate trials of 30-min duration to determine the maximal lactate steady-state (MLSS). The LT and MLSS were used to partition the intensity spectrum for each individual in three domains of intensity: moderate, heavy, and severe. Results V[Combining Dot Above]O2max in women and men was 3.06±0.41 L·min-1 and 4.10±0.56 L·min-1, respectively. LT and MLSS occurred at a greater %V[Combining Dot Above]O2max and %HRmax in women compared to men (P<0.05). The large ranges in both sexes at which LT and MLSS occurred on the basis of %V[Combining Dot Above]O2max (LT=45-74%; MLSS=69-96%), %WRpeak (LT=23-57%; MLSS=44-71%), and %HRmax (LT=60-90%; MLSS=75-97%) elicited large variability in the number of individuals distributed in each domain at the fixed-percentages examined. Conclusions Contemporary gold-standard methods for exercise prescription based on fixed-percentages of maximum values conform poorly to exercise intensity domains and thus do not adequately control the metabolic stimulus. Corresponding author: Dr. Juan M Murias, Assistant Professor, Faculty of Kinesiology, University of Calgary, KNB 434, 2500 University Drive NW, Calgary, Alberta, Canada, T2N 1N4, +1 (403) 220-7955, jmmurias@ucalgary.ca Funding from NSERC Canada (RGPIN-2016-03698) and the Heart & Stroke Foundation of Canada (#1047725) supported this study. We would like to thank the participants of this study. None of the authors has any conflict of interest to declare. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 27 August 2019 © 2019 American College of Sports Medicine

Body Composition as Mediator between the Physical Fitness on Bone Mass during Growth Introduction and Purpose To examine the effect of cardiorespiratory fitness (CRF) and muscle power output (MPO) on bone mass of prepubertal and pubertal children using lean mass (LM) and percentage of fat mass (%FM) as mediator variables. The hypothesis was that both LM and %FM would be independent mediators of the relationships during the sexual maturation period. Methods We analyzed 200 children [88 boys and 112 girls (11.5±2.0 years)]. Body composition was analysed by bone densitometry and, indirect calorimetry and cycle-ergometer were used to calculate VO2peak (ml·kg−1·min−1) and MPO (W) during an incremental exercise test. Sample was divided by pubertal status. Results In the prepubertal group, LM and %FM acted independently as mediators in the relationship between bone mass and CRF or MPO (22%-25% for LM and 37%-50% for %FM respectively). In pubertal children, LM acted as mediator at 37%. Conclusion Although the independent mediator role of LM and %FM in the associations between CRF or MPO and bone mass was present during the prepubertal stage, only LM remain its mediator role in these associations during the postpubertal period. Therefore, with growth and sexual maturation, the full effect of LM seems to increase, while the influence of %FM seems to disappear. Correspondence author: Ignacio Ara, PhD, GENUD Toledo Research Group University of Castilla-La Mancha, Avda Carlos III s/n, 45071 Toledo, Spain, Phone: +34 925 268 800 Ext 5543, [ignacio.ara@uclm.es] This study was supported by the Consejo Superior de Deportes - High Council for Sports in Spain (CSD-089/UPB10/11), the Biomedical Research Networking Center on Frailty and Healthy Aging (CIBERFES) and FEDER funds from the European Union (CB16/10/00477). IRG received a PhD grant from the University of Castilla-La Mancha “Pre-doctoral contracts for the training of research personnel in the framework of the I+D+I Plan, co-financed by the European Social Fund (2014/10340). MMG has received a PhD grant from the Ministry of Education, Culture and Sport, Spain (AP2010-5476). Conflict of interest: The authors have no conflicts of interest relevant to this article to disclose. Accepted for Publication: 24 June 2019 © 2019 American College of Sports Medicine

Inhaled Prostacyclin on Exercise Echocardiographic Cardiac Function in Preserved Ejection Fraction Heart Failure Introduction/Purpose Treatments that improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) have shown no benefits for those with heart failure with preserved ejection fraction (HFpEF). Our study aimed to investigate the impact of inhaled iloprost on myocardial performance during exercise in HFpEF. Methods The study participants were enrolled from the ILO-HOPE trial (NCT03620526), a prospective randomized, double-blind, placebo-controlled study that was designed to investigate the effects of iloprost on cardiovascular haemodynamics during exercise in patients with HFpEF. Subjects were randomized 1:1 to inhalation of iloprost or placebo for 5 minutes. Two-dimensional transthoracic echocardiography with high temporal resolution was implemented to measure LV longitudinal strain, LV diastolic function and RV function both at rest and during supine exercise at 20-watt workload. Results Left ventricular global longitudinal strain (LV GLS) in response to exercise increased more in iloprost group (LV GLS, -24.96 ± 1.20 vs. -20.75 ± 3.00, p<0.001). Iloprost also resulted in greater increment of LV GLS during exercise (ΔLV GLS, +6.02 ± 1.39 vs. +3.44 ± 0.80, p<0.001). Moreover, iloprost use was associated with enhancement of LV diastolic function, RV systolic function and relief of pulmonary hypertension during exercise. Conclusions In patients with HFpEF, inhaled iloprost favourably improved myocardial performance during exercise by increasing LV GLS reserve, decreasing LV diastolic filling load, and reducing stress-induced pulmonary hypertension and thereby improving RV systolic function. Larger studies are needed to validate the result and long-term benefits of iloprost in patients with HFpEF. The first two authors contributed equally to this paper Address for correspondence: Cho-Kai Wu, MD, PhD, Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital No. 7, Chung-Shan South Road, Taipei 100, Taiwan, Email: chokaiwu@stanford.edu; wuchokai@gmail.com, Phone: 886-2-23123456; Fax: 886-2-82317099 This work was supported in part by the National Science Council of the Republic of China (108-2314-B-002-201-MY2). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The authors declare that there is no conflict of interest associated with this manuscript. The results of the study to not constitute endorsement by ACSM and are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 23 August 2019 © 2019 American College of Sports Medicine

The Impact of Exercise Timing on Glycemic Control: A Randomized Clinical Trial Despite the acknowledgement of exercise as a cornerstone in the management of Type 2 Diabetes (T2D), the importance of exercise timing has only recently been considered. Purpose This study sought to determine the effect of diurnal exercise timing on glycemic control in individuals enrolled in a 12-week supervised multi-modal exercise training program. A secondary aim was to determine the effect of diurnal exercise timing on the circadian rhythm of wrist skin temperature. Methods Forty sedentary, overweight adults (age: 51[SD 13]years; BMI: 30.9[SD 4.2]kg/m2; women: n=23) with and without (n=20) T2D diagnosis were randomly allocated to either a morning (amEX) or evening (pmEX) exercise training group. The supervised 12-week (3 days/week) program, comprised 30 minutes of moderate intensity walking and 4 resistance-based exercises (3 sets, 12-18 repetitions each). Glycemic outcomes (glycated haemoglobin, HbA1c; fasting glucose, FG; postprandial glucose, PPG) wrist skin temperature were assessed at baseline and post-intervention. Results Exercise training improved (main effect of time: all p<0.01) all glycemic outcomes, however, this was independent of allocation to either the amEX (Hedge’s g: 0.23-0.90) or pmEX (Hedge’s g: 0.16-0.90) group. Accordingly, the adopted exercise training program did not alter the circadian rhythm of skin temperature. When only T2D individuals were compared, amEX demonstrated greater effects (all Hedge’s g) on HbA1c (amEX: 0.57; pmEX: 0.32), FG (amEX: 0.91; pmEX: 0.53) and PPG (amEX: 1.12; pmEX: 0.71) but was not statistically different. Conclusions Twelve weeks of multi-modal exercise training improved glycemic control and postprandial glycemic responses in overweight non-T2D and T2D individuals. However, no distinct glycemic benefits or alterations in circadian rhythm were associated with morning versus evening exercise, when performed three times per week in this cohort. Trial Registration: ANZCTR ACTRN12616001172493 Corresponding Author: Timothy J. Fairchild, School of Psychology and Exercise Science, Murdoch University, 90 South Street, Murdoch WA 6150, +61 (08) 9360 2959, t.fairchild@murdoch.edu.au ST is supported by an Australian Government Research Training Program (RTP) Scholarship. No additional sources of funding were declared by the remaining authors. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by ACSM. Accepted for Publication: 12 August 2019 © 2019 American College of Sports Medicine

Skeletal Effects of Nine Months of Physical Activity in Obese and Healthy-weight Children Purpose Obesity during adolescence has multi-system health consequences. The objective of this work was to determine whether pre-adolescent overweight/obese children’s bones respond to a 9-month physical activity intervention by increasing bone density similar to healthy-weight children. Methods Participants included overweight/obese (BMI >85%) and healthy weight (15% < BMI <85%) preadolescents (8-9years old). Participants in the physical activity group participated in a 9-month physical activity curriculum every day after school. The wait-list control group received no intervention. Both groups had overweight/obese children and healthy-weight controls. Whole body bone mineral content (BMC), area, and bone mineral apparent density (BMAD) were assessed using dual X-ray absorptiometry) at the beginning and end of the 9-month trial in the physical activity and control group. Results Overweight/obese pre-adolescent children had higher BMAD than healthy weight children (p<0.001 for spine, leg, and whole body). However, the density/weight (BMAD/lean mass) was lower in overweight/obese children than in healthy weight children indicating the density of bones in overweight/obese children may not compensate sufficiently for the excessive load due to weight. The change in BMAD over 9 months was greater in healthy weight children than overweight/obese children in the whole body and leg, but not the lumbar spine. Physical activity caused a site-specific increase in bone density, affecting the legs more than the lumbar spine, but there was no significant difference in the effect of exercise between the healthy weight and overweight/obese group. Conclusions The smaller change in BMAD over the 9 months and lower BMAD per unit lean mass in overweight/obese compared to healthy weight children may indicate a slower rate of bone mass accrual, which may have implications for bone health during skeletal growth in obese/overweight children. Corresponding Author: Dr. Sandra J Shefelbine, Northeastern University, Boston, MA, Email: s.shefelbine@northeastern.edu The Fitness Improves Thinking in Kids (FITKids) trial was supported by the National Institutes of Health (HD055352 to CH). The Fitness Improves Thinking in Kids (FITKids) 2 trial was supported by the National Institutes of Health (HD069381 to CH and AK). Additional support for this project was provided by the National Institute of Food and Agriculture, US Department of Agriculture, (2011-67001-30101). The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation, and statement that results of the present study do not constitute endorsement by ACSM. Conflict of Interest: The authors have nothing to disclose. Accepted for Publication: 15 August 2019 © 2019 American College of Sports Medicine

Individual Response to Standardized Exercise: Total and Abdominal Adipose Tissue Purpose (1) Determine the effect of exercise amount and intensity on the proportion of individuals for whom the adipose tissue (AT) response is above the minimal clinically important difference (MCID); and (2) Examine whether clinically meaningful anthropometric changes reflect individual AT responses above the MCID. Methods Men (n=41) and women (n=62) (52.7 ± 7.6 years) were randomized to control (N=20); low amount low intensity (LALI, N=24); high amount low intensity (HALI, N=30); and high amount high intensity (HAHI, N=29) treadmill exercise for 24 weeks. AT changes were measured by MRI. 90% confidence intervals for each individual’s observed response were calculated as the observed score ± 1.64*TE (technical error of measurement). Results For visceral AT, HAHI and HALI had a greater proportion of individuals whose AT change and 90% CI were beyond the MCID compared to controls (p<0.006). For all other AT depots, all exercise groups had significantly more individuals whose changes were beyond the MCID compared to controls. Of those who achieved a waist circumference (WC) or body weight reduction ≥ the MCID, 76-93% achieved abdominal, abdominal subcutaneous, and visceral AT changes ≥ the MCID. Conclusion Increasing exercise amount and/or intensity may increase the proportion of individuals who achieve clinically meaningful visceral AT reductions. WC or body weight changes beyond a clinically meaningful threshold are predictive of clinically meaningful abdominal adiposity changes. Corresponding author: Robert Ross, PhD, R. Kin, FACSM, FAHA, FCAHS, School of Kinesiology and Health Studies, 28 Division Street, Queen’s University, Kingston, Ontario, Canada, K7L 3N6, E-mail: rossr@queensu.ca, Phone: (613) 533-6583, Fax: (613) 533-2580 The study was supported by the Canadian Institutes of Health Research (Grant OHN-63277). The authors declare no conflict of interest. The results of the present study do not constitue endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 19 August 2019 © 2019 American College of Sports Medicine

A Randomized Community-based Exercise Training Trial in African American Men: ARTIIS Purpose To examine the impact of a community-based exercise training intervention on cardiometabolic outcomes in African American men who have a family history of type 2 diabetes. Methods The Aerobic Plus Resistance Training and Insulin Sensitivity in African American Men (ARTIIS) study randomized participants into either an exercise training intervention or an information only control group for 5 months. The exercise training intervention consisted of 150 minutes of moderate intensity aerobic activity and two days of resistance training per week, consistent with the current federal physical activity guidelines. Participants in the control group received monthly newsletters featuring topics focused heavily on type 2 diabetes education and prevention. Outcome data were analyzed using repeated measures analysis of covariance (ANCOVA) models and incorporating both intention-to-treat and per-protocol principles. Results Adherence to the aerobic and resistance training prescriptions were between 77% and 79%. Despite significant within group improvements in glucose and insulin levels (fasting, 2-hour, 2-hour minus baseline) and Homeostatic Model 2-Insulin Resistance, there were not significant between group differences. There was a marginally significant between group difference for Homeostatic Model 2-Beta (p < 0.06), and significant between group differences in peak cardiorespiratory fitness (p < 0.001) and waist circumference (p = 0.03). Conclusion These findings suggest that exercise training in accordance with the current national recommendations is effective in improving some health parameters in middle-aged African American men who have a family history of type 2 diabetes, but did not have a significant impact on glycemic status. Trial registration: The study is registered in clinicaltrials.gov [NCT01787617]. Corresponding author: Robert L. Newton Jr., PhD, Associate Professor, Director, Physical Activity and Ethnic Minority Health Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808, Email: Robert.Newton@pbrc.edu This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK09523301]. The work was also supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The study sponsor was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. No conflicts of interest are declared. The results of the study do not constitute endorsement by the American College of Sports Medicine. Accepted for Publication: 26 August 2019 © 2019 American College of Sports Medicine

activPAL and ActiGraph Assessed Sedentary Behavior and Cardiometabolic Health Markers Purpose To establish whether associations between sedentary behaviour and cardiometabolic health differ when assessed by thigh-worn and waist-worn accelerometry. Methods Participants were recruited from several areas in the United Kingdom. Sedentary behaviour was assessed using the activPAL worn on the thigh and ActiGraph worn on the waist. Average total (TST), prolonged (bouts ≥30minutes; PST) and breaks (BST) in sedentary time were calculated. Cardiometabolic health markers included: adiposity (body fat) and surrogate markers of adiposity ((waist circumference, body mass index (BMI)), lipids (total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, triglycerides), blood pressure and glucose (fasting, 2 h and glycated haemoglobin (HbA1c)). A clustered cardiometabolic risk score was calculated. Linear regression analysis examined the associations with cardiometabolic health. Results 1457 participants (mean age (± standard deviation): 59.38 ± 11.85 years; 51.7% male; mean BMI: 30.19 ± 5.59 kg/m2) were included in the analyses. ActivPAL and ActiGraph sedentary variables were moderately correlated (0.416 - 0.511, p<0.01), however all variables were significantly different from each other (p<0.05). Consistency was observed across devices in the direction and magnitude of associations of TST and PST with adiposity, surrogate markers of adiposity, HDL, triglycerides and cardiometabolic risk score and for BST with adiposity, surrogate markers of adiposity and cardiometabolic risk. Differences across devices were observed in associations of TST and PST with diastolic blood pressure, for TST with 2 h glucose and for BST with HDL. No other associations were observed for any other health marker for either device. Conclusion Results suggest that associations with cardiometabolic health are largely comparable across the two common assessments of sedentary behaviour but some small differences may exist for certain health markers. Corresponding author: Dr Charlotte Edwardson, Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, LE5 4PW, United Kingdom The analysis was supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre which is a partnership between University Hospitals of Leicester NHS Trust, Loughborough University and the University of Leicester, and the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care–East Midlands (NIHR CLAHRC–EM). The STAND study was funded by a grant from the Medical Research Council (UK) under the National Prevention Research Initiative (Project #91409).The Walking Away from Diabetes study was funded by the National Institute for Health Research (NIHR) Collaboration in Applied Health Research and Care for Leicestershire, Northamptonshire and Rutland (CLAHRC LNR) and the Collaboration for Leadership in Applied Health Research and Care – East Midlands (CLAHRC – EM). The PROPELS trial was funded by the Health Technology Assessment (HTA) Programme, National Institute for Health research. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or Department of Health. There are no other conflicts of interest. The results of the present study do not constitute endorsement by the ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 22 August 2019 © 2019 American College of Sports Medicine