McGee et al. Trials          (2019) 20:484 
https://doi.org/10.1186/s13063-019-3611-1
STUDY PROTOCOL Open Access
High-intensity exercise to promote
accelerated improvements in
cardiorespiratory fitness (HI-PACE): study
protocol for a randomized controlled trial
Joshua E. McGee1,2* , Savanna G. Barefoot1,2, Nicole R. Gniewek1,2, Patricia M. Brophy4, Angela Clark4,
Gabriel S. Dubis1,2,4, Terence E. Ryan3,4,6, Joseph A. Houmard1,2, Paul Vos5, Thomas D. Raedeke1 and
Damon L. Swift1,2
Abstract
Background: African Americans have a disproportionate prevalence and incidence of type 2 diabetes compared
with Caucasians. Recent evidence indicates that low cardiorespiratory fitness (CRF) level, an independent risk factor
for type 2 diabetes, is also more prevalent in African Americans than Caucasians. Numerous studies in Caucasian
populations suggest that vigorous exercise intensity may promote greater improvements in CRF and other type 2
diabetes risk factors (e.g., reduction of glucose/insulin levels, pulse wave velocity, and body fat) than moderate
intensity. However, current evidence comparing health benefits of different aerobic exercise intensities on type 2
diabetes risk factors in African Americans is negligible. This is clinically important as African Americans have a
greater risk for type 2 diabetes and are less likely to meet public health recommendations for physical activity than
Caucasians. The purpose of the HI-PACE (High-Intensity exercise to Promote Accelerated improvements in
CardiorEspiratory fitness) study is to evaluate whether high-intensity aerobic exercise elicits greater improvements in
CRF, insulin action, and arterial stiffness than moderate-intensity exercise in African Americans.
Methods/Design: A randomized controlled trial will be performed on overweight and obese (body mass index of
25–45 kg/m2) African Americans (35–65 years) (n = 60). Participants will be randomly assigned to moderate-intensity
(MOD-INT) or high-intensity (HIGH-INT) aerobic exercise training or a non-exercise control group (CON) for 24
weeks. Supervised exercise will be performed at a heart rate associated with 45–55% and 70–80% of VO2 max in
the MOD-INT and HIGH-INT groups, respectively, for an exercise dose of 600 metabolic equivalents of task (MET)-
minutes per week (consistent with public health recommendations). The primary outcome is change in CRF.
Secondary outcomes include change in insulin sensitivity (measured via an intravenous glucose tolerance test),
skeletal muscle mitochondrial oxidative capacity (via near-infrared spectroscopy), skeletal muscle measurements (i.e.,
citrate synthase, COX IV, GLUT-4, CPT-1, and PGC1-?), arterial stiffness (via carotid-femoral pulse wave velocity), body
fat, C-reactive protein, and psychological outcomes (quality of life/exercise enjoyment).
(Continued on next page)
* Correspondence: mcgeej16@students.ecu.edu
1Department of Kinesiology, East Carolina University, 388 Ward Sports
Medicine Building, Greenville, NC 27858, USA
2Human Performance Laboratory, East Carolina University, 388 Ward Sports
Medicine Building, Greenville, NC 27858, USA
Full list of author information is available at the end of the article
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
McGee et al. Trials          (2019) 20:484 Page 2 of 14
(Continued from previous page)
Discussion: The anticipated results of the HI-PACE study will provide vital information on the health effects of
high-intensity exercise in African Americans. This study will advance health disparity research and has the potential
to influence future public health guidelines for physical activity.
Trial registration: ClinicalTrials.gov identifier: NCT02892331. Registered on September 8, 2016.
Keywords: Methodology, Exercise intensity, African American, Cardiorespiratory fitness, Insulin sensitivity, Arterial
stiffness
Background sensitivity to insulin (increased GLUT-4 expression)
The American Diabetes Association (ADA) identifies ra- [36, 37]. Thus, lower CRF levels in AAs may contrib-
cial health disparities in type 2 diabetes (T2D) as a major ute to the racial health disparities in T2D.
public health concern [1]. T2D prevalence in African Data examining CAs suggest that high-intensity aer-
Americans (AAs) is one of the greatest in the US; AAs obic training results in greater improvements in CRF, in-
have about 1.7-fold higher rates compared with their sulin action, and arterial stiffness compared with
Caucasian American (CA) counterparts (females: 13.6% moderate intensity [26, 38, 39]. Thus, high-intensity ex-
versus 7.4%; males: 14.1% versus 8.0%, respectively) [2]. ercise may improve the low-CRF, stiffened-artery, and
An ADA position statement from 2016 [3] recognized insulin-resistant disposition observed in obese AAs more
the importance of physical activity to prevent T2D, as readily because of greater shear rates in the vasculature,
low levels are associated with greater T2D incidence. recruitment of type II fibers, and greater energy expend-
The prevalance of AAs meeting public health recom- iture rates than moderate intensity. There are, however,
mendations for physical activity is considerably lower no current randomized controlled trials comparing the
than CA adults (56.5% versus 67.5%, respectively) [4]. health benefits of different exercise intensity training
Despite established racial disparities in T2D risk, AAs programs in AAs despite the greater T2D risk in AAs
are under-represented in exercise research (i.e., sample than CAs.
sizes inadequate for sub-group analyses and few ran- The goal of the HI-PACE (High-Intensity exercise to
domized clinical trials specifically examining AAs). This Promote Accelerated improvements in CardiorEspira-
lack of data critically limits the federal Physical Activity tory fitness) study is to evaluate the effects of exercise
Guidelines from making accurate conclusions on the ef- intensity on CRF, insulin action, and arterial stiffness in
fects of physical activity on health outcomes in AAs [5]. AAs at high risk for T2D. The purpose of the following
Low cardiorespiratory fitness (CRF) is an independent article is to describe the design, rationale, and method-
risk factor for T2D incidence [6–11]. However, an incre- ology of the HI-PACE study.
mental dose response has been observed between CRF
level and T2D incidence [8, 12]. Categorically defined Specific objectives
“low CRF” is associated with the greatest risk of T2D, The objective of the HI-PACE study is to determine
and a greater proportion of AAs have “low CRF” than whether high-intensity aerobic exercise training results
CAs [8, 10, 13–27]. Higher intensities of aerobic exercise in greater improvements in CRF, insulin action, arterial
show promise in eliciting a larger magnitude of improve- stiffness, mitochondrial function, adiposity, and quality
ment in insulin sensitivity compared with moderate of life compared with moderate intensity. Thus, the pri-
intensity. Moreover, arterial stiffness, another racial dis- mary outcome of the HI-PACE study is the change in
parity identified in AAs, has shown a greater decline CRF following the intervention. Main secondary out-
from high-intensity exercise than moderate intensity comes include change in insulin sensitivity (measured
[28–30]. An additional contributor to the T2D racial dis- via an intravenous glucose tolerance test [IVGTT]), skel-
parities is the lower oxidative characteristics and subse- etal muscle mitochondrial oxidative capacity (via near-
quent reduced insulin sensitivity of skeletal muscle in infrared spectroscopy [NIRS]), skeletal muscle measure-
AAs compared with CAs [13, 26, 31–33]. AAs tend to ments (i.e., citrate synthase, COX IV, GLUT-4, CPT-1, and
have a greater proportion of type II muscle fibers (i.e., PGC1-?), arterial stiffness (via carotid-femoral pulse wave
less oxidative, vascularized, lower proportion of GLUT-4 velocity [PWV]), body fat, C-reactive protein, and psycho-
transporters, and more insulin-resistant than type I fi- logical outcomes (quality of life/exercise enjoyment).
bers) compared with CAs [32, 34, 35]. A major adapta- Participants will be randomly assigned to one of three
tion to aerobic training is the shift in both type I and II groups: (1) moderate-intensity (MOD-INT), (2) high-in-
fibers toward more oxidative properties (e.g., increased tensity (HIGH-INT), or (3) a non-exercise control
mitochondria size, density, and enzymes) and increased (CON) group for 24 weeks. The exercise volume for
McGee et al. Trials          (2019) 20:484 Page 3 of 14
both exercise groups will be 600 metabolic equivalents Table 1 Major inclusion and exclusion criteria
of task (MET)-minutes per week (3–4 sessions per Inclusion criteria
week), which is consistent with the current public health Age 35–65 years
guidelines (500–1,000 MET-minutes) [5]. Participants in
Sex Men and women
the MOD-INT group will exercise at the heart rate asso-
ciated with 45 55% of maximal oxygen consumption Overweight/obese 25.0–45.0 kg/m
2
– body mass index
(VO2 max), and participants in the HIGH-INT group Physically inactive Sedentary/low active, not participating in
will exercise at the heart rate associated with 70–80% regular aerobic or resistance exercise < 20
VO2 max. Fitbit Flex accelerometers (Fitbit Inc., San min, ?2 days/week for last 3 months
Francisco, CA, USA) will be worn on the wrist by partic- African American Self-identify as African American
ipants in all randomization groups to objectively moni- Informed consent Willingness and capability to provide written
tor non-exercise physical activity during the intervention consent and to understand the exclusion
(devices will be removed during training sessions). criteria
Exclusion criteria
Methods/Design Diabetes Diagnosed type 1 or type 2 diabetes or
Inclusion/exclusion criteria fasting glucose ?126mg/dL
The main inclusion and exclusion criteria for HI-PACE Cardiovascular disease Diagnosed congestive heart failure, serious
are shown in Table 1. The HI-PACE study is designed to or disorders arrhythmias, peripheral vascular disease with
intervene in sedentary, overweight, and obese AAs at intermittent claudication, previous stroke, ormyocardial infarction
high risk for T2D. Thus, we plan to enroll 60 sedentary,
Resting blood pressure Excessively high resting systolic (>180
overweight, and obese AA adults (body mass index mmHg) or diastolic (>100 mmHg) blood
[BMI] of 25.0–45.0 kg/m2 and age of 35–65 years). All pressure. Participants taking blood pressure
participants will be sedentary/low active and not partici- medications at time of recruitment are
permitted to enroll.
pating in exercise training at the time of enrollment (<
20min and ?2 days per week for the last 3 months). Blood lipids Total cholesterol ?240mg/dL, low-density
lipoprotein cholesterol ?160mg/dL, or
Major exclusion criteria for the HI-PACE study include triglycerides ?300mg/dL
diagnosed type 1 or 2 diabetes (or fasting glucose of Other exclusionary Chronic or reoccurring neuromuscular,
more than 125 mg/dL or use of diabetes medication), medical conditions respiratory, gastrointestinal, neurological, HIV,
known cardiovascular diseases (e.g., heart failure, serious or psychiatric conditions. Musculoskeletal
arrhythmias, and peripheral vascular disease), previous conditions affecting exercise. Currenttreatment for mental illness or hospitalization
stroke or myocardial infarction, excessively high resting from mental illness within previous 5 years.
systolic (>180mm Hg) or diastolic (>100mm Hg) blood Autoimmune or collagen vascular diseases.
pressure, significant medical conditions, life-threatening Other medical conditions that are consideredlife-threatening or that can be provoked
conditions, pregnancy or plans to become pregnant, and from exercise training
other medical conditions that are contraindicated for Other exclusion criteria Pregnancy or plans to become pregnant.
exercise training. Additionally, individuals who plan to Currently engaging in or plans to engage in
diet, engage in weight loss, or demonstrate non-compli- weight loss or dieting program. Addition of
medication or dosage (or both) unstable in
ance during screening visits will be excluded. past 3 months. Previous bariatric surgery or
The study protocol has been approved by the East current weight loss medications. Plans to
Carolina University (ECU) institutional review board leave the Pitt County (NC) area for more
than 2 weeks during the next 6 months.
and is registered on ClinicalTrials.gov (NCT02892331). Non-compliance in wearing pedometer or
This study protocol was prepared on the basis of the demonstration of high risk for non-
SPIRIT (Standard Protocol Items: Recommendations for compliance/dropout during screening
Interventional Trials) guidelines. This SPIRIT Checklist
is available as Additional file 1. contacts in the Pitt County, North Carolina area (e.g.,
churches, physician offices, libraries, and barbershops). In
Recruitment and pre-screening addition, a study website will be created to provide basic
A detailed summary of the study visits is described in study information and to serve as a mechanism for web-
Table 2. Recruitment material will be disseminated screening potential participants. Web-screening will be
through newspaper (general readership and an AA-spe- performed by using an online survey in which basic inclu-
cific newspaper), targeted social media advertisement (e.g., sion/exclusion criteria questions can be completed and
Facebook and Instagram), email sent through company subsequently reviewed by study staff. This online survey is
employee listservs (i.e., ECU, Pitt Community College, created by using an online research database, REDCap
and Greenville government), and local organizational (Nashville, TN, USA) [40], which is connected to the main
McGee et al. Trials          (2019) 20:484 Page 4 of 14
Table 2 Detailed summary of data collection at study visits and review prescribed medications (individuals will be re-
Screening visit and informed consent quired to bring in prescribed medications for verification).
- Informational session about study requirements For inclusion/exclusion purposes, height and weight (with-
out shoes) will be measured to calculate BMI (in kilograms
- Obtain informed consent
per square meters), and seated resting blood pressure will be
- Verify inclusion criteria (i.e., BMI and blood pressure) assessed via an automated blood pressure monitor (HEM-
- Physical exam/review of medications 907XL, Omron Healthcare Co., Ltd., Kyoto, Japan).
- Non-exercise physical activity via activPAL Individuals will be screened for ample time to partici-
- Exercise calendar and Barriers screening forms pate in the exercise intervention by filling out an exer-
- Complete metabolic panel, lipids, insulin, C-reactive protein, and cise calendar form, in which they will be asked to
blood chemistries identify specific days and times (and back-up times) they
Baseline are available to exercise at our facility (Additional file 2:
- PWV, muscle biopsy, IVGTT, and NIRS Appendix A). Staff will also conduct a standardized
interview with potential participants in which (a) weekly
- SF-36 and FFQ
time commitments, (b) responsibilities for family care
- Body weight, blood pressure, anthropometry, DEXA, and maximal (i.e., child and elder), (c) distances of home and work
exercise test
from our exercise facility, (d) personal motivations for
Randomization exercising, (e) levels of familial support, and (f ) any
- CON, MOD-INT, or HIGH-INT group other barrier(s) that would affect study adherence will be
Mid-intervention (12 weeks) evaluated (Additional file 2: Appendix B). The exercise
- Waist circumference calendar and interview are intended to screen out indi-
- Body weight viduals depicting high risk for non-compliance or drop-
out (or both) during the 24-week study. Previous studies
- Maximal exercise test
using similar methodologies exhibited high exercise
Follow-up (24 weeks) training adherence and study retention [41, 42].
- Non-exercise physical activity via activPAL Individuals who are still eligible at this point will wear
- PWV, muscle biopsy, IVGTT, and NIRS a Fitbit Flex (Fitbit Inc.) and an activPAL accelerometer
- SF-36 and FFQ (PAL Technologies Ltd., Glasgow, UK) for 7 continuous
- Complete metabolic panel, lipids, insulin, C-reactive protein, and days to assess baseline non-exercise physical activity
blood chemistries level. The Fitbit Flex will be worn on the non-dominant
- Body weight, blood pressure, anthropometry, DEXA, and maximal wrist to obtain data on steps, miles, intensity, and calorie
exercise test expenditure each day of wear (blinded to individual).
Abbreviations: BMI body mass index, CON non-exercise control (group), DEXA Study staff will apply the activPAL by rolling a nitrile
dual-energy x-ray absorptiometry, FFQ food frequency questionnaire, HIGH-INT sleeve over the entire device and wrap an 8 × 10 cm
high-intensity exercise (group), IVGTT intravenous glucose tolerance test, MOD-
INT moderate-intensity exercise (group), NIRS near-infrared spectroscopy, PWV sheet of transparent medical dressing completely around
pulse wave velocity, SF-36 short-form health survey it to act as a waterproof barrier. Staff will rub an alco-
hol-based prep pad around the site, place the distal end
study database. Interested individuals can also contact HI- of the activPAL toward the knee, and apply a separate
PACE staff by calling the study phone number or by dir- sheet of medical dressing over the monitor to complete
ectly emailing the research coordinator. After this, study application to the leg (waterproofing method). The activ-
staff will phone-screen individuals for major aspects of the PAL accelerometer will be worn on the individual’s mid-
inclusion/exclusion criteria and provide additional infor- thigh and will not be removed for the entire 7 days. The
mation about study participation. Individuals who are eli- activPAL measures postural aspects of time spent sitting/
gible and still interested after phone screening will lying down, standing, and walking in hours per day as well
progress to screening visit 1. as energy expenditure (MET-hours per day), steps per day,
and number of sit-to-stand transitions.
Screening visits The HI-PACE study will use a REDCap database to
Screening visits will be conducted at the East Carolina Heart store all information collected from screening visits (e.g.,
Institute by the research coordinator. During screening visit contact/demographic information and blood lab results)
1, the research coordinator will describe all properties of and to track physical activity data during the physical ac-
study participation, answer questions from individuals, and tivity assessment. During each day the devices are worn,
obtain informed consent. Following consent, the research REDCap surveys will be sent automatically to individuals’
coordinator will screen participants for the full inclusion/ex- email address to ask whether the activPAL and Fitbit de-
clusion criteria, collect contact/demographic information, vices were worn on the previous day and whether there
McGee et al. Trials          (2019) 20:484 Page 5 of 14
were any extended periods of non-wear time. The purposes baseline and follow-up (week 24). At mid-intervention
of the survey are to (1) increase the accuracy of the physical (week 12), CRF, resting blood pressures, and anthropom-
activity assessment by being able to eliminate days affected etry (i.e., body mass, waist circumference, and BMI) will
by non-wear and (2) prompt individuals to wear the devices be re-evaluated. Measurements of arterial stiffness, muscle
consistently. Since changes in non-exercise physical activity biopsy, IVGTT, and NIRS will be obtained in this order
can confound exercise-related changes in outcome mea- during the same visit (baseline and follow-up), whereas
sures [43, 44], it is necessary to ensure that participants in CRF, anthropometry, and body composition will be
the HI-PACE study can regularly wear the devices. obtained during the same visit of a separate week. The pri-
Following completion of the baseline physical activity as- mary outcome will be obtained at the Human Perform-
sessment (7 days), individuals will return in the fasted state ance Laboratory in the Ward Sports Medicine Building,
to the East Carolina Heart Institute for screening visit 2 in whereas the secondary outcomes will be obtained at the
the morning. The study nurse will perform a fasting blood East Carolina Heart Institute. Randomization into a study
draw and immediately send the sample to a clinical labora- group will occur upon completion of all baseline assess-
tory (LabCorp Inc., Burlington, NC, USA) for complete ments. For an overview of the schedule of enrollment,
metabolic panel, lipid panel, insulin level, and blood chemis- randomization, intervention, and assessments, see Fig. 2
tries. Pre-menopausal women will be required to complete a for the completed SPIRIT figure.
pregnancy test. The Fitbit and activPAL will be retrieved for
accelerometer data to be downloaded and recorded in the Primary outcome: change in maximal oxygen uptake
study database. Upon completion of the screening visits, in- (VO2 max)
dividuals will be scheduled for the baseline assessment visit. The primary outcome measurement is CRF due to the
well-established association between CRF levels and risk
Assessment visits (baseline, mid-intervention, and follow-up) of T2D [8, 10, 11, 27]. We will measure CRF as VO2 max
A flowchart of the present study is shown in Fig. 1. Pri- (the gold standard) from a maximal exertion treadmill test
mary (i.e., CRF) and secondary outcome measures (i.e., ar- under the supervision of a physician. Maximal exercise
terial stiffness, mitochondrial measures, insulin sensitivity, testing will be conducted on a treadmill (Cardiac Science
skeletal muscle oxidative capacity, quality of life, and TM65, Davis Medical Electronics, Bothell, WA, USA)
food-frequency questionnaires [FFQ]) will be obtained at under a modified Balke protocol. For the warm-up,
Fig. 1 Flowchart of study visits in the HI-PACE (High-Intensity exercise to Promote Accelerated improvements in CardiorEspiratory fitness) study
McGee et al. Trials          (2019) 20:484 Page 6 of 14
Fig. 2 Study schedule of enrollment, intervention, and assessments. Abbreviations: AIx augmentation index, CON non-exercise control group, DEXA
dual-energy x-ray absorptiometry, FFQ food frequency questionnaire, HIGH-INT high-intensity exercise group, IVGTT intravenous glucose tolerance
test, MOD-INT moderate-intensity exercise group, NIRS near-infrared spectroscopy, PA physical activity, PWV pulse wave velocity, SF-36 short-form
health survey, t1 baseline, t2 mid-intervention (week 12), t3 follow-up (week 24)
participants will initially walk at a speed of 2.0 mph at 0% centrifuged and stored at ?80 °C until sample analysis
grade for 2min. Subsequently, we will increase treadmill for glucose and insulin. Insulin sensitivity index will be
speed to 3.0 mph to begin the treadmill test. During the determined through a minimal model [45]. Follow-up
test, we will increase the treadmill grade by 2.5% every 2 IVGTT will be assessed within 18–24 h of the MOD-
min until volitional exhaustion. Gas exchange (i.e., VO2 INT and HIGH-INT participants’ last exercise session.
and carbon dioxide production (VCO2)) and pulmonary
ventilation will be measured continuously by using a
TrueOne 2400 Metabolic Measurement Cart (Parvo Arterial stiffness
Medics, Salt Lake City, UT, USA). Heart rate, blood pres- Carotid-femoral PWV and aortic blood pressure parame-
sure, rating of perceived exertion, and electrocardiogram ters will be measured by using a SphygmoCor XCEL
will be monitored and recorded before, during, and after (AtCor Medical, Itasca, IL, USA). Carotid-femoral PWV,
the exercise test. The electrocardiogram will be cleared by an index of the degree of arterial stiffness, is the gold-
the study physician prior to participant randomization. A standard measurement of arterial stiffness [46]. Arterial
valid maximal exercise test will meet two of three end cri- stiffness measurements will occur during the morning in
teria: (1) elevated respiratory exchange ratio (RER) a quiet, temperature-controlled room at baseline and fol-
(?1.10), (2) plateauing of VO2, or (3) within ± 5 beats per low-up. Prior to each measure, participants will refrain
minute of age-predicted maximal heart rate. from vigorous exercise, tobacco, caffeine, and alcohol for
at least 12 h as well as large meals for at least 6 h. Partic-
Secondary outcome measures ipants will take their prescribed medications which will
Secondary outcome measures include change in insulin be logged and repeated at follow-up. The methodology
action, arterial stiffness, mitochondrial function, body for arterial stiffness measurements will adhere to a pos-
fat, C-reactive protein, and psychological surveys. ition stand by the American Heart Association [47].
For aortic blood pressure and stiffness measurements,
Insulin sensitivity participants will be in the seated position for a 5-min
Insulin sensitivity will be assessed at baseline and follow- rest period. Following rest, aortic blood pressure (e.g.,
up (24 h following the last exercise session for the brachial blood pressures and aortic blood pressures) and
MOD-INT and HIGH-INT groups) via an IVGTT. After stiffness (e.g., augmentation index and wave reflection)
collection of fasting blood samples, glucose (dextrose parameters will be obtained on the basis of acquisition
50%) will be injected into a catheter placed in the ante- of brachial artery pressure waveforms with the applica-
cubital vein at a dose of 0.3 g/kg body weight. Subse- tion of a generalized transfer function to derive the cen-
quently, blood samples will be obtained at the following tral aortic pressure waveform, from which estimates of
time points: 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 25, 30, aortic blood pressures are generated. Three measure-
40, 50, 60, 70, 80, 90, 100, 120, 140, 160, and 180 min. ments will be performed for aortic blood pressure pa-
Insulin will be injected at minute 20 of the test at a dose rameters with a 1-min rest period between each
of 0.025 U/kg body weight. Blood samples will be measurement.
McGee et al. Trials          (2019) 20:484 Page 7 of 14
Subsequently, PWV will be obtained in the supine 50mg of muscle tissue will be homogenized (T8 Ultra
position following a 15-min rest. During rest, body sur- Turrax; IKA, Wilmington, NC, USA) in 20 volumes of
face measurements will be measured via a Gulick tape cell lysis buffer (50 mM HEPES, 12 mM sodium pyro-
measure (Baseline, Fabrication Enterprises, White Plains, phosphate, 100 mM sodium fluoride, 100 mM ethylene-
NY, USA) in triplicate to determine the distance traveled diaminetetraacetic acid, 10 mM sodium orthovanate, 1%
by the pulse wave between the carotid and femoral ar- Triton X-100) supplemented with a protease and phos-
tery sites. Study staff will palpate and mark the carotid phatase inhibitor cocktails (Sigma-Aldrich, St. Louis,
artery pulse (between the larynx and sternocleidomas- MO, USA). Lysates will be sonicated for 5 s, rotated for
toid muscle in the neck), the sternal notch (superficial about 1 h at 4 °C, and centrifuged at 13,500 × g for 15
landmark of aortic arch), and femoral artery pulse (over min at 4 °C. Protein concentration for each sample hom-
the ventral thigh halfway between the pubic symphysis ogenate will be determined via a commercially available
and anterior superior iliac spine) [48]. The mean dis- bicinchoninic acid protein assay kit (Pierce, Rockford,
tance for each site will be used for PWV calculation. IL, USA). Aliquots containing 30 ?g of total protein will
Pressure waveforms at the carotid arterial site will be ac- be diluted in 4x Laemmli Buffer (Bio-Rad Laboratories,
quired via applanation tonometry and electrocardio- Inc., Hercules, CA, USA) with 5% ?-mercaptoethanol
graphic gating and the femoral arterial site will be (?ME) at a 3:1 ratio prior to heating at 70 °C for 10min.
simultaneously acquired by using the oscillometric de- Denatured samples will be brought to room temperature,
vice within the SphygmoCor XCEL. The PWV measure- loaded onto a 10% polyacrylamide gel, separated by SDS-
ment will be conducted in duplicate, and the mean of PAGE, and transferred to nitrocellulose membranes.
these measurements will be the reported value. Both Membranes will be blocked with Odyssey Blocking Buffer
measurements must be within 0.5 m per second to be (OBB; Li-Cor, Lincoln, NE, USA) for 1 h and incubated
considered acceptable for data purposes. If the two mea- with primary antibodies. Membranes will be washed with
surements differ by more than 0.5 m per second, a third TBST (Tris-buffered saline, 0.1% Tween 20) and incu-
measurement will be obtained, and the reported value bated with an anti-rabbit or anti-mouse fluorophore-con-
will be the median of the three measurements. jugated secondary antibody (1:20,000; Li-Cor) in OBB
supplemented with 0.1% Tween-20 for 1 h. Then the
Mitochondrial function membranes will be washed with TBST followed by TBS
A percutaneous muscle biopsy (100–200 mg of tissue) prior to being scanned on the Odyssey CLx Imaging Sys-
will be obtained by using sterile techniques at baseline tem (Li-Cor) and quantified on Image Studio software
and follow-up from the vastus lateralis with a 5-mm (V4.0.21; Li-Cor). GAPDH will be used as a loading
Bergström muscle biopsy cannula with suction (Stille control.
Surgical Instruments, Eskilstuna, Sweden), as previously Citrate synthase activity will be determined with a col-
described [49]. Briefly, participants will lie supine with orimetric reaction by using reagents in a commercial kit
legs extended (0° flexion) and two operators will spray (Sigma CD0720), as in a previous study [51]. A 10- to
ethyl chloride on the biopsy site and administer 1% lido- 15-mg piece of muscle will be diluted 20-fold in a buffer
caine at each level of subcutaneous tissue, stopping containing 100mM KH2PO4 and 0.05% bovine serum al-
superficial to the fascia. Following 2–3 min to allow for bumin and homogenized at 4 °C by using the Ultra Tur-
the local anesthetic effects, a 1-cm incision will be made rax. Homogenates will undergo four freeze-thaw cycles
through the skin and subcutaneous tissues, parallel to before experimentation. Protein content will be mea-
the femur, until an incision is made through the muscle sured by using the bicinchoninic acid assay, and citrate
fascia. The operator will use the biopsy cannula to locate synthase activity will be assessed with reagents provided
the fascia incision site and advance the needle past the in the commercial kit (Sigma CS0720), which uses a col-
fascia, angled downward toward the floor to rapidly clip orimetric reaction to measure the reaction rate of acetyl
and collect the muscle sample with suction by the sec- coenzyme A and oxaloacetic acid.
ond operator. Following the biopsy, the sample will be
trimmed of visible adipose tissue, weighed on a scale In vivo skeletal muscle mitochondrial oxidative capacity
(AL54, Mettler-Toledo, Columbus, OH, USA), and snap- As an additional measure of mitochondrial function, in
frozen in liquid nitrogen to be stored at ?80 °C until vivo skeletal muscle mitochondrial oxidative capacity
analysis at study completion. will be measured non-invasively via NIRS at baseline
Peroxisome proliferator-activated receptor gamma co- and follow-up. This NIRS approach measures the recov-
activator 1-alpha (PGC1-?), COX IV, GLUT-4, and ery kinetics of skeletal muscle oxygen consumption
CPT-1 content will be determined; these proteins were (mVO2) following brief exercise and has demonstrated
selected as they are downstream of PGC1-? and repre- strong correlations with current in vivo and ex vivo
sent distinct steps in oxidative metabolism [50]. About gold-standard measurements of mitochondrial function
McGee et al. Trials          (2019) 20:484 Page 8 of 14
(i.e., magnetic resonance spectroscopy and muscle bi- Blood sample collection
opsy) [52, 53]. We will implement a NIRS testing A venous blood sample will be drawn with a 21-gauge
protocol similar to that of Ryan et al. [53]. NIRS data needle with the participant in the fasted state at baseline
will be obtained by using an OxiplexTS (ISS, Cham- and follow-up. A total of 21 mL of blood will be drawn
paign, IL, USA), a frequency-domain tissue oximeter. by the study nurse and will immediately be sent to a
Briefly, the OxiplexTS is equipped with two independ- clinical laboratory (LabCorp Inc.) for a complete meta-
ent data acquisition channels and eight infrared diode bolic panel, lipid panel, insulin level, and blood chemis-
lasers (four emitting at 691 nm and four at 830 nm) tries. Prior to glucose injection during the baseline and
and a detector within each (emitter-detector distances follow-up IVGTT, we will collect vials of archive plasma,
of 2.0–4.0 cm). The absolute values of oxygenated serum, and red blood cells to be stored at ?80 °C for fu-
hemoglobin (O2Hb) and deoxygenated hemoglobin ture analysis. We also will send an additional serum sep-
(HHb) will be calculated in micromoles in accordance arator tube to LabCorp Inc. for measurement of C-
with the instructions of the manufacturer. Data will reactive protein.
be collected at 4 Hz. Both NIRS probes will be cali-
brated prior to each test by using a phantom with Anthropometry and body composition
known optical properties once the device warms up Body weight will be measured in the fasted state via a
for at least 20 min. calibrated scale (DigiTol 8510, Mettler-Toledo) (re-
For each NIRS measurement, participants will be su- corded to the nearest tenth of a kilogram). Dual energy
pine on a padded table and have both legs extended (0° x-ray absorptiometry (GE Lunar Prodigy Advance, Fair-
flexion). A skinfold caliper (Lange, Beta Technology, field, CT, USA) will be used to measure body compos-
Santa Cruz, CA, USA) will be used to measure subcuta- ition (fat and fat-free mass) at baseline and follow-up.
neous adipose tissue thickness at the probe site (about Waist circumference will be measured via a Gulick tape
10 cm above the patella). The NIRS probe will be se- measure at the natural waist (halfway point from the in-
cured to the skin at the vastus lateralis site with double- ferior border of the rib cage and the superior point of
sided adhesive tape and Velcro straps. Additionally, a the iliac crest). Participants will be instructed to stand
blood pressure cuff (Hokanson SC-10D or SC-10 L, D.E. straight and upright with their feet together and arms to
Hokanson, Inc., Bellevue, WA, USA) will be placed their side. Study staff will mark each landmark and
proximal to the NIRS probe as high as anatomically pos- measure the distance to determine the proper measure-
sible to prevent unwanted signal noise from cuff infla- ment site. For each measure, study staff will confirm that
tion. A 15-gal air compressor (Model D55168, Dewalt, (1) the tape is parallel to the floor, (2) the tape touches
Baltimore, MD, USA) set to 30 psi will power a rapid-in- the entire circumference of the participant, (3) the tape
flation system (Hokanson E20, D.E. Hokanson) to con- is not compressing any abdominal tissue, (4) the tape is
trol the blood pressure cuff. not within abdominal folds, and (5) the measurement is
Upon securement of the probe and cuff, participants recorded following a normal exhalation by the partici-
will complete a short-duration (about 10–30 s), sub- pant. Duplicate waist circumference measurements will
maximal, repeated knee extension or isometric quadri- be obtained. If measurements are ± 0.5 cm, the reported
cep exercise (or both) to increase mVO2. Following value will be the average of the two. If measurements
exercise, the recovery kinetics of mVO2 will be deter- differ more than 0.5 cm, a third measurement will be
mined from a series of repeated arterial occlusions assessed, and the reported value will be the average of
(275–300 mm Hg) for about 5–7 min in duration by the three measurements. Waist circumference will be
using the following inflation/deflation timing: 5 s in- evaluated at baseline, mid-intervention, and follow-up.
flated/5 s deflated for about 90 s and then 10 s inflated/
10 s deflated for the remainder of test. The beginning Non-exercise physical activity levels
and end of each occlusion will be marked for calcula- Non-exercise physical activity data will be monitored in
tions of mVO2 from the deoxygenated hemoglobin/ all randomization groups by using a Fitbit Flex activity
myoglobin signal (i.e., slope during occlusion). The tracker throughout the intervention period. Each group
post-exercise mVO2 data will be fit to a mono-expo- will be blinded to the number of steps accrued and
nential function to calculate the rate constant, which is instructed not to change their non-exercise physical ac-
directly related to the mitochondrial respiratory cap- tivity levels from baseline. Prior to each exercise session,
acity [52]. Three trials of exercise and occlusion proce- the Fitbit device will be removed from the participant
dures will be performed and the results will be (to not mix exercise and non-exercise physical activity
averaged. Baseline and follow-up NIRS data will be ana- data) and synced to the Fitbit software to upload their
lyzed via custom-written routines in MATLAB R2017b non-exercise physical activity levels. Participants in the
(MathWorks, Natick, MA, USA). CON group will sync their data at home by using the
McGee et al. Trials          (2019) 20:484 Page 9 of 14
Fitbit software and be monitored by study staff to ensure how individuals feel at a specific moment in time. The
compliance. Automated REDCap surveys will be emailed scale ranges from ?5 (very bad) to +5 (very good), and 0
three times per week to all participants to inquire about represents neutral feelings. Study staff will collect Feel-
Fitbit wear. Participants will be instructed to fill out ing Scale data every 5 min during the first exercise ses-
these surveys to validate consistent device wear as this sion of every week of the exercise intervention.
will allow staff to input non-exercise physical activity
data on a weekly basis. This process helps to ensure con- Randomization
sistent daily wearing of the device and to determine Participants will be randomly assigned to the non-exer-
whether the participant did not wear the Fitbit for ex- cise control (CON), moderate-intensity (MOD-INT), or
tended periods of time. high-intensity (HIGH-INT) group upon completion of
Study staff will use a database program (Fitabase, all baseline assessments and approval by the study phys-
Small Steps Labs, San Diego, CA, USA) to centralize all ician. The study biostatistician will generate a
non-exercise physical activity data (i.e., total daily steps, randomization list to allocate participants in a 1:1:1 ratio
minutes of light, moderate and vigorous physical activity, to study groups. The randomization process will be per-
miles traveled, and estimated kilocalorie energy expend- formed by an individual separate from the research
iture). All non-exercise physical activity data synced to team, who has no interaction with the study participants
Fitabase will be stored in a custom-made REDCap data- or access to HI-PACE study data. All other research staff
base. Study staff will input all non-exercise physical ac- (including the principal investigator) will not have access
tivity data on a weekly basis. to the randomization list. Once a participant has com-
pleted all baseline assessments, study staff will email the
Dietary composition participant’s identification number and gender to the in-
Dietary intake will be tracked at baseline and follow-up dividual. The participant will be assigned to the next
via the Block FFQ [54]. The FFQ consists of 105 catego- group on the randomization list. Upon randomization,
rized items and assesses both frequency of consumption the intervention period will begin the following week. A
and portion size selections, in which participants will re- study flowchart is shown in Fig. 1.
call their typical eating habits within the previous 3
months at baseline and follow-up time points. The ques- Aerobic exercise training
tionnaire estimates daily intake values of kilocalories and All exercise sessions will be supervised by study staff
select macronutrients and micronutrients and also cal- and performed on a treadmill (Precor TRM 885, Precor
culates servings by food group. The research coordinator Inc., Woodinville, WA, USA) to sustain control of en-
will instruct participants at screening visit 1 to maintain ergy expenditure from exercise. Participants in the
current dietary habits and not to begin intentional diet- MOD-INT group will exercise at a target heart rate asso-
ing for the entirety of the study. Additionally, study staff ciated with 45–55% VO2 max, and participants in the
will remind all participants on a weekly basis not to change HIGH-INT group will exercise at a target heart rate as-
their eating habits during the intervention. The FFQ serves sociated with 70–80% VO2 max. The heart rate range
as a semi-quantitative measure to ensure that dietary habits for each participant will be determined on the basis of
are not changed throughout the intervention. the maximal exercise test (baseline and mid-interven-
tion). The full exercise dose for both groups will be 600
Psychological parameters MET-minutes per week, which is consistent with current
The short form health survey (SF-36) [55] will be used public health guidelines [5]. Since participants will be
to measure quality of life at both baseline and follow-up. sedentary at baseline, we will increase the exercise dose
Exercise enjoyment will be assessed via the Physical Ac- incrementally throughout the study to avoid potential
tivity Enjoyment (PACE) Scale [56] and the Feeling Scale adverse events during exercise. Initially, the exercise
[57]. As secondary outcomes, the impact of exercise in- dose will be 300 MET-minutes during week 1 and will
tensity on these affective responses (i.e., feelings of increase by 50 MET-minutes per week until the max-
overall pleasure/displeasure and enjoyment) plays an im- imum exercise volume of 600 MET-minutes is reached
portant role in physical activity participation and adher- at week 9. The exercise dose will remain at 600 MET-
ence [58–60]. The PACE Scale is composed of eight minutes until conclusion of the intervention (Fig. 3). We
items rated on a 7-point semantic differential scale in will calculate the number of MET-minutes exercised on
which “4” represents a neutral position. The PACE Scale the basis of treadmill speed/grade and the participants’
will be collected every 4 weeks during the exercise inter- weight by using the standard American College of Sports
vention. Affective responses to exercise will be assessed Medicine (ACSM) walking equation [61]. Custom-made
by having participants complete the Feeling Scale. The Excel spreadsheets will be used to determine exercise
Feeling Scale is a single-item, 11-point scale that assesses time for each session on the basis of (1) the required
McGee et al. Trials          (2019) 20:484 Page 10 of 14
Fig. 3 Ramping protocol of required MET-minutes in both the MOD-INT and HIGH-INT groups in the HI-PACE study. Abbreviations: HIGH-INT high-
intensity exercise group, HI-PACE High-Intensity exercise to Promote Accelerated improvements in CardiorEspiratory fitness, MET Metabolic
equivalents of task, MOD-INT moderate-intensity exercise group
weekly MET-minutes, (2) the participants’ weight, (3) ex- in an exercise program outside of the study. Addition-
ercise speed/grade, and (4) the amount of expected ses- ally, we will ask participants about any changes to their
sions per week (3–4 sessions per week). prescribed medications on a weekly basis.
At the first exercise session of each week, study staff Prior to starting exercise, participants will rest for 5
will weigh participants (without shoes) on a calibrated min in the seated position, after which study staff will
scale and remind them not to alter their diet or engage measure systolic/diastolic blood pressures by using a
McGee et al. Trials          (2019) 20:484 Page 11 of 14
mercury sphygmomanometer and record resting heart expenditure (EE) rate via indirect calorimetry (TrueOne
rate via a Zephyr Bioharness 3 monitor (Medtronic, An- 2400) at the participant’s prescribed exercise speed and
napolis, MD, USA). Each participant will be instructed to grade on a treadmill [42, 63, 64]. This exercise economy
complete a 5-min warm-up on the treadmill at a low test will be performed on weeks 1, 3, and 5 and then
speed (about 2.0 miles per hour) at 0% grade. Following monthly until the conclusion of the intervention. The
completion of the warm-up, participants will begin their rate of EE determined through indirect calorimetry will
prescribed exercise by adjusting the treadmill’s speed or be divided by estimated EE determined from the ACSM
grade or both. During the supervised exercise, heart rate walking equation to develop a correction factor (i.e., ac-
will be monitored continuously by using the Bioharness tual EE rate/predicted EE rate). This correction factor
monitor to confirm exercise intensity and participants will will be used to (1) adjust the EE calculated from the
be required to remain within their target heart range ACSM equation to more accurately implement the exer-
(MOD-INT: heart rate associated with 45–55% VO2 max; cise prescription which corresponds to 600 MET-minutes
HIGH-INT: heart rate associated with 70–80% VO2 max). per week, (2) adjust participants’ exercise session time ac-
Heart rate, along with participants’ subjective rating of cording to potential changes in metabolic or biomechan-
perceived exertion (RPE) via the Borg scale, will be re- ical efficiency (or both) from exercise training, and (3)
corded every 5min [62]. The Feeling Scale will also be re- verify required MET-minutes exercised by increasing or
corded every 5min on the first exercise session of each decreasing exercise session time accordingly.
week. Study staff will keep mobile laptop carts nearby the
exercising participant(s) and will use custom-made Excel Training data management
spreadsheets to quantify (1) the number of MET-minutes Exercise volume adherence will be defined as MET-mi-
accumulated during exercise and number of MET-mi- nutes exercised divided by required MET-minutes. Exer-
nutes remaining in the session and (2) mean heart rate cise intensity adherence will be quantified as time within
and RPE of the session and (3) calculate the amount of the required target heart rate range divided by total exer-
time remaining in the current session. The spreadsheet cise time. Exercise compliance will be defined as the num-
calculates these variables in real time and can compensate ber of sessions attended divided by the number of sessions
for potential adjustments, such as increasing or decreasing required. The research team will actively monitor exercise
treadmill speed or grade or both, during the exercise volume/intensity adherence, compliance, and other indi-
session. cators of intervention fidelity (e.g., target heart rate com-
Once completed with the exercise session, participants pliance, wear rate of accelerometer, participant morale,
will perform a 5-min cool-down at a similar intensity as and progression rate of speed/grade) on a weekly basis in
the warm-up. Subsequently, participants will rest for 5 study meetings. In all randomization groups, Fitbit wear
min in the seated position for recording of post-exercise compliance will be monitored throughout the 6-month
heart rate and systolic/diastolic blood pressures. Lastly, intervention. Weekly reports will be compiled from the
study staff will input all exercise session data (i.e., total study databases to monitor and review the compliance
exercise duration, MET-minutes, caloric expenditure, and adherence rates of all participants.
miles traveled, average speed, grade, heart rate, RPE, and
percentage of time participant exercised within target Statistical considerations
heart rate range) into the database. The results of the current pilot study will be used to ad-
For each exercise session, the mean heart rate will be vise the design (effect size/statistical power) of a larger
calculated by using Omnisense Analysis version 5.0 soft- prospective intervention. The response variable for the
ware (Medtronic). The Bioharness monitors continu- primary outcome is change in VO2 max. The three treat-
ously record heart rate data on a second-by-second ment groups—CON, MOD-INT, and HIGH-INT—will
basis. Thus, to collect the mean heart rate for each ses- be compared in terms of baseline VO2 max by using
sion, study staff will analyze heart rate data only during side-by-side boxplots and the corresponding numeric
exercise by creating a time-specific sub-session annota- summaries along with mean and standard deviation.
tion within the Omnisense software to exclude non-ex- This will be repeated for post-treatment values of VO2
ercise heart rate data from calculation. This process will max and for VO2 max differences of post-treatment and
more accurately calculate exercise intensities during baseline. If there are distributional concerns, log trans-
training sessions since heart rate will be measured con- formation of VO2 max will be considered. Unless there
tinuously as opposed to intervals (e.g., every 5 min). are extreme outliers or severe heteroscedasticity, one-
way analysis of variance (ANOVA) will be used for infer-
Exercise economy ence regarding the primary outcome. The two-sample t
To address potential variability in exercise economy at a test (without assuming equal variances) along with the
given workload, study staff will directly measure energy associated confidence intervals will be used for
McGee et al. Trials          (2019) 20:484 Page 12 of 14
differences in group means; confidence intervals for dif- psychological parameters of quality of life and enjoyment
ferences in group means obtained from the one-way of exercise will be obtained, which will help determine
ANOVA will also be reported. whether high-intensity aerobic exercise is a feasible
The above steps used for VO2 max (the primary out- strategy over a 6-month period to improve health out-
come) will be repeated for each of the numeric variables comes in AAs. We anticipate that the results of the HI-
used for secondary outcomes. These variables are change PACE study will provide clear evidence of health bene-
in insulin sensitivity, mitochondrial protein content, cit- fits from high-intensity exercise, successful recruitment
rate synthase activity, skeletal muscle mitochondrial oxi- tactics, and favorable exercise adherence data in at-risk
dative capacity, arterial stiffness parameters, body fat AAs. The pilot data will be necessary to conduct a lar-
percentage, and C-reactive protein. Data will be analyzed ger-sample-sized exercise intensity study in AAs with
on an intention-to-treat basis. adequately powered primary and secondary variables.
The ordinal variables of exercise enjoyment and qual-
ity of life will be dichotomized into “no improvement” Trial status
and “improvement”. Fisher’s exact test will be used to Participant recruitment for this study began in Novem-
obtain an overall P value, and restriction to two of the ber 2016 and is ongoing. The study recruitment is ex-
treatment groups will provide estimated odds ratios and pected to end in October 2019.
the associated confidence intervals.
The three groups will be compared by using the follow- Additional files
ing demographic and other variables that may be related
to exercise, change in VO2 max, or one of the other re- Additional file 1: SPIRIT (Standard Protocol Items: Recommendations for
sponse variables: age, sex, body weight, BMI, waist cir- Interventional Trials) 2013 checklist. (DOC 122 kb)
cumference, body fat percentage, fat mass, fat-free mass, Additional file 2: Appendices (Appendix A: Exercise calendar form;
Appendix B: Barriers screening form). (DOCX 52 kb)
cholesterol, triglycerides, and blood pressures. If differ-
ences among the treatment groups in terms of one or
Abbreviations
more of these variables are deemed important, adjust- AA: African American; ACSM: American College of Sports Medicine;
ments to the above comparisons will be made by using ADA: American Diabetes Association; ANOVA: Analysis of variance; BMI: Body
higher-order ANOVA, analysis of covariance (ANCOVA), mass index; CA: Caucasian American; CON : Non-exercise control (group);
CRF: Cardiorespiratory fitness; ECU: East Carolina University; EE: Energy
or linear regression or a combination of these. expenditure; FFQ: Food frequency questionnaire; GLUT-4: Glucose transporter
Power ranges from 0.85 for 15 participants per group type 4; HIGH-INT : High-intensity exercise (group); HI-PACE: High-Intensity
to 0.96 for 20 participants per group using ?0.112, 0.124, exercise to Promote Accelerated improvements in CardiorEspiratory fitness;
IVGTT: Intravenous glucose tolerance test; MET: Metabolic equivalents of task;
and 0.200 L/min as the means for the three groups on MOD-INT : Moderate-intensity exercise (group); mVO2: Skeletal muscle
the basis of previous data [65], a common standard devi- oxygen consumption; NIRS: Near-infrared spectroscopy; OBB: Odyssey
ation of 0.250 L/min, and significance level ? = 0.05. We Blocking Buffer; PACE: Physical activity enjoyment scale; PGC1-?: Peroxisome
proliferator-activated receptor gamma coactivator 1-alpha; PWV: Pulse wave
expect attrition to be about 10–15% and so enrollment velocity; RPE: Rating of perceived exertion; SPIRIT: Standard Protocol Items:
of 60 participants (20 per group) will be sufficient for Recommendations for Interventional Trials; T2D: Type 2 diabetes; TBST: Tris-
the primary outcome. buffered saline, 0.1% Tween 20; VO2 max: Maximal oxygen consumption
All statistical analyses will be performed by using stat- Acknowledgments
istical software in R version 3.5.1. [66]. The resultant We would like to thank Alec Chaves for providing language for muscle
mean change and standard deviation of the change of sample analysis and the undergraduate student assistants at East Carolina
outcome measures (if indicative of enhance cardiometa- University for assisting in exercise training and recruitment.
bolic improvements in the HIGH-INT compared with Authors’ contributions
the MOD-INT and CON groups) will be used for power JEM was responsible for recruitment, data collection and analysis, and
calculations to determine the necessary sample size of a manuscript writing. SGB, NRG, and PMB were responsible for recruitment,
management of the study, data collection and analysis, and critical revision
larger study. of the manuscript. AC and GSD were responsible for data collection and
critical revision of the manuscript. TER and JAH were responsible for design
Discussion of the study, data collection and analysis, and critical revision of the
manuscript. PV and DLS calculated the power and the sample size,
The HI-PACE study has high public health relevance developed the statistical analysis plan for outcomes, and will conduct final
due to the increased disease burden of T2D and the lack analyses. TDR was responsible for design of the psychological aspects of the
of exercise training studies in AAs. HI-PACE will be the study and critical revision of the manuscript. DLS conceived, designed, and
managed the study and was responsible for recruitment, data collection and
first study to compare two exercise training programs analysis, and manuscript writing. All of the authors reviewed and approved
on multiple T2D and cardiovascular risk factors in over- the final manuscript.
weight and obese AAs. HI-PACE has the potential to in-
Funding
fluence future physical activity recommendations and This study is funded by a grant from the National Institutes of Health–
advance health disparity research. Additionally, valuable National Institute of Diabetes and Digestive and Kidney Diseases
McGee et al. Trials          (2019) 20:484 Page 13 of 14
(1R03DK105297-01A1). The funders had no role in the design of the study or Middle-aged Men. Arch Intern Med. 1996;156:1307–14. https://doi.org/10.1
in the collection, analysis, or interpretation of data or in writing the 001/archinte.1996.00440110073010.
manuscript. 12. Wei M. Relationship Between Low Cardiorespiratory Fitness and Mortality in
Normal-Weight, Overweight, and Obese Men. JAMA. 1999;282:1547. https://
Availability of data and materials doi.org/10.1001/jama.282.16.1547.
Not applicable. 13. Swift DL, Staiano AE, Johannsen NM, Lavie CJ, Earnest CP, Katzmarzyk PT, et
al. Low Cardiorespiratory Fitness in African Americans: A Health Disparity
Ethics approval and consent to participate Risk Factor? Sport Med. 2013;43:1301–13. https://doi.org/10.1007/s40279-
Written consent will be obtained from every participant. The present study 013-0092-3.
was performed in accordance with the Declaration of Helsinki. The East 14. Wang C-Y, Haskell WL, Farrell SW, LaMonte MJ, Blair SN, Curtin LR, et al.
Carolina University & Medical Center Institutional Review Board approved the Cardiorespiratory Fitness Levels Among US Adults 20–49 Years of Age:
study protocol. Findings From the 1999–2004 National Health and Nutrition Examination
Survey. Am J Epidemiol. 2010;171:426–35 Available from: http://aje.
Consent for publication oxfordjournals.org/content/171/4/426.abstract.
Not applicable. 15. Ceaser TG, Fitzhugh EC, Thompson DL, Bassett DRJ. Association of
Physical Activity, Fitness, and Race: NHANES 1999–2004. Med Sci
Competing interests Sports Exerc. 2013;45:286–93 Available from: http://journals.lww.com/
The authors declare that they have no competing interests. acsm-msse/Fulltext/2013/02000/Association_of_Physical_Activity,_
Fitness,_and.10.aspx.
Author details 16. Duncan GE, Li SM, Zhou XH. Cardiovascular fitness among U.S. adults:
1Department of Kinesiology, East Carolina University, 388 Ward Sports NHANES 1999–2000 and 2001–2002. Med Sci Sports Exerc. 2005;37:1324–8.
Medicine Building, Greenville, NC 27858, USA. 2Human Performance 17. Kokkinos P, Myers J, Kokkinos JP, Pittaras A, Narayan P, Manolis A, et al. Exercise
Laboratory, East Carolina University, 388 Ward Sports Medicine Building, Capacity and Mortality in Black and White Men. Circulation. 2008;117:614–22
Greenville, NC 27858, USA. 3Department of Physiology, Brody School of Available from: http://circ.ahajournals.org/content/117/5/614.abstract.
Medicine, Greenville, NC 27858, USA. 4The East Carolina Diabetes & Obesity 18. Kokkinos P, Myers J, Nylen E, Panagiotakos DB, Manolis A, Pittaras A, et al.
Institute, East Carolina University, Greenville, NC 27858, USA. 5Department of Exercise Capacity and All-Cause Mortality in African American and Caucasian
Biostatistics, East Carolina University, Greenville, NC 27858, USA. 6Present Men With Type 2 Diabetes. Diabetes Care. 2009;32:623–8 Available from:
affiliation: Department of Applied Physiology & Kinesiology, University of http://care.diabetesjournals.org/content/32/4/623.abstract.
Florida, Gainesville, FL 32611, USA. 19. Ribisl PM, Lang W, Jaramillo SA, Jakicic JM, Stewart KJ, Bahnson J, et al.
Exercise Capacity and Cardiovascular/Metabolic Characteristics of
Received: 8 February 2019 Accepted: 23 July 2019 Overweight and Obese Individuals With Type 2 Diabetes. Diabetes Care.
2007;30:2679–84 Available from: http://care.diabetesjournals.org/content/3
0/10/2679.abstract.
References 20. Sidney S, Haskell WL, Crow R, Sternfeld B, Oberman A, Armstrong MA, et al.
1. American Diabetes Association. 2018 State and Federal Legislative & Symptom-limited graded treadmill exercise testing in young adults in the
Regulatory Priorities: Diabetes Research and Programs. 2018. CARDIA study. Med Sci Sports Exerc. 1992;24:176–83 Available from: http://
2. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, journals.lww.com/acsm-msse/Fulltext/1992/02000/Symptom_limited_
et al. Heart Disease and Stroke Statistics—2018 Update: A Report From the graded_treadmill_exercise_testing.4.aspx.
American Heart Association. Circulation. 2018;137:e67–492 Available from: 21. Zeno SA, Kim-Dorner SJ, Deuster PA, Davis JL, Remaley AT, Poth M.
http://circ.ahajournals.org/content/circulationaha/137/12/e67.full.pdf. Cardiovascular fitness and risk factors of healthy African Americans and
3. Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Caucasians. J Natl Med Assoc. 2010;102:28–35 Available from: http://www.
Physical activity/exercise and diabetes: A position statement of the ncbi.nlm.nih.gov/pubmed/20158133.
American Diabetes Association. Diabetes Care. 2016;39:2065–79. 22. Hunter GR, Chandler-Laney PC, Brock DW, Lara-Castro C, Fernandez JR,
4. Centers for Disease Control and Prevention. Prevalence of Self-reported Gower BA. Fat Distribution, Aerobic Fitness, Blood Lipids, and Insulin
physically active adults––United States. MMWR. 2007;57:1297–300. Sensitivity in African-American and European-American Women. Obesity.
5. Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines 2010;18:274–81. https://doi.org/10.1038/oby.2009.229.
Advisory Committee Report, 2008. Washington, DC: U.S. Department of 23. Hunter GR, Weinsier RL, Darnell BE, Zuckerman PA, Goran MI. Racial
Health and Human Services, 2008. differences in energy expenditure and aerobic fitness in premenopausal
6. Wei M, Gibbons LW, Mitchell TL, Kampert JB, Lee CD, Blair SN. The women. Am J Clin Nutr. 2000;71:500–6 Available from: http://www.ajcn.org/
Association between Cardiorespiratory Fitness and Impaired Fasting Glucose content/71/2/500.abstract.
and Type 2 Diabetes Mellitus in Men. Ann Intern Med. 1999;130:89–96. 24. Hunter GR, Weinsier RL, McCarthy JP, Enette Larson-Meyer D, Newcomer BR.
https://doi.org/10.7326/0003-4819-130-2-199901190-00002. Hemoglobin, muscle oxidative capacity, and VO2 max in African-American
7. Boulé NG, Kenny GP, Haddad E, Wells GA, Sigal RJ. Meta-analysis of the and Caucasian women. Med Sci Sports Exerc. 2001;33:1739–43.
effect of structured exercise training on cardiorespiratory fitness in Type 2 25. Swift DL, Johannsen NN, Lavie CJ, Earnest CP, Johnson WD, Blair SN, et al.
diabetes mellitus. Diabetologia. 2003;46:1071–81. https://doi.org/10.1007/ Racial Differences in the Response of Cardiorespiratory Fitness to Aerobic
s00125-003-1160-2. Exercise Training in Caucasian and African American Postmenopausal
8. Sui X, Hooker SP, Lee I-M, Church TS, Colabianchi N, Lee C-D, et al. A Women. J Appl Physiol. 2013;114:1375–82.
Prospective Study of Cardiorespiratory Fitness and Risk of Type 2 Diabetes 26. Swift DL, Johannsen NM, Earnest CP, Newton RL, McGee JE, Church TS.
in Women. Diabetes Care. 2008;31:550–5 Available from: http://care. Cardiorespiratory Fitness and Exercise Training in African Americans. Prog
diabetesjournals.org/content/31/3/550.abstract. Cardiovasc Dis. 2017;60:96–102. https://doi.org/10.1016/j.pcad.2017.06.001.
9. Sawada SS, Lee I-M, Naito H, Noguchi J, Tsukamoto K, Muto T, et al. Long- 27. Sawada SS, Lee I-M, Muto T, Matuszaki K, Blair SN. Cardiorespiratory Fitness
Term Trends in Cardiorespiratory Fitness and the Incidence of Type 2 and the Incidence of Type 2 Diabetes: Prospective study of Japanese men.
Diabetes. Diabetes Care. 2010;33:1353–7 Available from: http://care. Diabetes Care. 2003;26:2918–22 Available from: http://care.diabetesjournals.
diabetesjournals.org/content/33/6/1353.abstract. org/content/26/10/2918.abstract.
10. Carnethon MR, Sternfeld B, Schreiner PJ, Jacobs DR, Lewis CE, Liu K, et al. 28. Ashor AW, Lara J, Siervo M, Celis-morales C, Mathers JC. Effects of Exercise
Association of 20-Year Changes in Cardiorespiratory Fitness With Incident Modalities on Arterial Stiffness and Wave Reflection: A Systematic Review
Type 2 Diabetes. Diabetes Care. 2009;32:1284–8 Available from: http://care. and Meta-Analysis of Randomized Controlled Trials. PLoS One. 2014;9:1–15.
diabetesjournals.org/content/32/7/1284.abstract. 29. Seo J-B, Chung W-Y, Kim S-H, Kim M-A, Zo J-H. Immediate impact of
11. Lynch J, Helmrich SP, Lakka TA, Kaplan GA, Cohen RD, Salonen R, et al. exercise on arterial stiffness in humans. World J Cardiovasc Dis. 2013;3:40–5.
Moderately Intense Physical Activities and High Levels of Cardiorespiratory Available from: http://www.scirp.org/journal/PaperDownload.aspx?DOI=
Fitness Reduce the Risk of Non-Insulin-Dependent Diabetes Mellitus in 10.4236/wjcd.2013.31009, https://doi.org/10.4236/wjcd.2013.31009.
McGee et al. Trials          (2019) 20:484 Page 14 of 14
30. Kang S-J, Kim E-H, Ko K-J. Effects of aerobic exercise on the resting heart 49. Shanely RA, Zwetsloot KA, Triplett NT, Meaney MP, Farris GE, Nieman DC.
rate, physical fitness, and arterial stiffness of female patients with metabolic Human Skeletal Muscle Biopsy Procedures Using the Modified Bergström
syndrome. Phys Ther Sci. 2016;28:1764–8. Technique. J Vis Exp. 2014;91:1–8 Available from: http://www.jove.com/
31. Ceaser T, Hunter G. Black and White Race Differences in Aerobic Capacity, video/51812/human-skeletal-muscle-biopsy-procedures-using-modified-
Muscle Fiber Type, and Their Influence on Metabolic Processes. Sport Med. bergstrom.
2015;45:615–23. https://doi.org/10.1007/s40279-015-0318-7. 50. Wen X, Wu J, Chang JS, Zhang P, Wang J, Zhang Y, et al. Effect of Exercise
32. Suminski RR, Mattern CO, Devor ST. Influence of Racial Origin and Skeletal Intensity on Isoform-Specific Expressions of NT-PGC-1? mRNA in Mouse
Muscle Properties on Disease Prevalence and Physical Performance. Sport Skeletal Muscle. Biomed Res Int. 2014;2014:402175:1–11.
Med. 2002;32:667–73 Available from: https://link.springer.com/article/1 51. Battaglia GM, Zheng D, Hickner RC, Houmard JA. Effect of exercise training
0.2165%2F00007256-200232110-00001. on metabolic flexibility in response to a high-fat diet in obese individuals
33. Staiano AE, Harrington DM, Johannsen NM, Newton RL, Sarzynski MA, Swift [Internet]. 2012. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/
DL, et al. Uncovering physiological mechanisms for health disparities in type PMC3532462/.
2 diabetes. Ethn Dis. 2015;25:31–7 Available from: http://europepmc.org/ 52. Ryan TE, Southern WM, Reynolds MA, McCully KK. A cross-validation of near-
abstract/MED/25812249. infrared spectroscopy measurements of skeletal muscle oxidative capacity
34. Tanner CJ, Barakat HA, Dohm GL, Pories WJ, MacDonald KG, Cunningham with phosphorus magnetic resonance spectroscopy. J Appl Physiol. 2013;
PRG, et al. Muscle fiber type is associated with obesity and weight loss. Am 115:1757–66 Available from: http://jap.physiology.org/cgi/doi/10.1152/
J Physiol - Endocrinol Metab. 2002;282:E1191–6 Available from: http:// japplphysiol.00835.2013.
ajpendo.physiology.org/content/282/6/E1191.abstract. 53. Ryan TE, Brophy P, Lin C-T, Hickner RC, Neufer PD. Assessment of in vivo
35. Ama PF, Simoneau JA, Boulay MR, Serresse O, Theriault G, Bouchard C. skeletal muscle mitochondrial respiratory capacity in humans by near-
Skeletal muscle characteristics in sedentary black and Caucasian males. J infrared spectroscopy: a comparison with in situ measurements. J Physiol.
Appl Physiol. 1986;61:1758–61 Available from: http://jap.physiology.org/ 2014;592:3231–41 Available from: http://doi.wiley.com/10.1113/jphysiol.2
content/61/5/1758.abstract. 014.274456.
36. Wang Y, Simar D, Fiatarone Singh MA. Adaptations to exercise training 54. Block G, Thompson FE, Hartman AM, Larkin FA, Guire KE. Comparison of
within skeletal muscle in adults with type 2 diabetes or impaired glucose two dietary questionnaires validated against multiple dietary records
tolerance: a systematic review. Diabetes Metab Res Rev. 2009;25:13–40. collected during a 1-year period. J Am Diet Assoc. 1992;92:686–93.
37. Zorzano A, Palacin M, Guma A. Mechanisms regulating GLUT4 glucose 55. Ware JE Jr, Sherbourne CD, Ware JE Jr, Sherbourne CD. The MOS 36-item
transporter expression and glucose transport in skeletal muscle. Acta Physiol short-form health survey (SF-36). I. Conceptual framework and item
Scand. 2005;183:43–58. selection. Med Care. 1992;30:473–83 Available from: http://www.jstor.org/
38. Swain DP, Franklin BA. Comparison of Cardioprotective Benefits of Vigorous stable/3765916.
Versus Moderate Intensity Aerobic Exercise. Am J Cardiol. 2006;97:141–7 Available 56. Kendzierski D, DeCarlo KJ. Physical Activity Enjoyment Scale: Two Validation
from: http://www.sciencedirect.com/science/article/pii/S0002914905016991. Studies. J Sport Exerc Psychol. 1991;13:50–64.
39. Roberts CK, Little JP, Thyfault JP. Modification of insulin sensitivity and 57. Hardy CJ, Rejeski WJ. Not What, But How One Feels: The Measurement of
glycemic control by activity and exercise. Med Sci Sports Exerc. 2013;45: Affect During Exercise. J Sport Exerc Psychol. 1989;11:304–17.
1868–77. 58. Raedeke TD. The Relationship Between Enjoyment and Affective Responses
40. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research to Exercise. J Appl Sport Psychol. 2007;19:105–15. https://doi.org/10.1080/1
electronic data capture (REDCap) – A metadata-driven methodology and 0413200601113638.
workflow process for providing translational research informatics support. J 59. McArthur LH, Raedeke TD. Race and sex differences in college student
Biomed Inform. 2009;42:377–81 Available from: http://www.ncbi.nlm.nih. physical activity correlates. Am J Heal Behav. 2009;33:80–90.
gov/pmc/articles/PMC2700030/. 60. Azizan A, Justine M, Kuan CS. Effects of a behavioral program on exercise
41. Swift DL, Dover SE, Nevels TR, Solar CA, Brophy PM, Hall TR, et al. The adherence and exercise self-efficacy in community-dwelling older persons.
intervention composed of aerobic training and non-exercise physical Curr Gerontol Geriatr Res. 2013;2013:1–9.
activity (I-CAN) study: Rationale, design and methods. Contemp Clin Trials. 61. American College of Sports Medicine. In: Whaley M, editor. ACSM’s
2015;45:435–42 Available from: http://www.sciencedirect.com/science/ Guidelines for Exercise Testing and Prescription. 8th ed. Baltimore:
article/pii/S1551714415301166. Lippincott Williams& Williams; 2010.
42. Myers CA, Johnson WD, Earnest CP, Rood JC, Tudor-Locke C, Johannsen 62. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc.
NM, et al. Examination of mechanisms (E-MECHANIC) of exercise-induced 1982;14:377–81.
weight compensation: Study protocol for a randomized controlled trial. 63. Donnelly JE, Honas JJ, Smith BK, Mayo MS, Gibson CA, Sullivan DK, et al.
Trials. 2014;15:1–12. Aerobic exercise alone results in clinically significant weight loss for men
43. Swift DL, Johannsen NM, Tudor-Locke C, Earnest CP, Johnson WD, Blair SN, and women: Midwest Exercise Trial-2. Obesity. 2013;21:E219–28. https://doi.
et al. Exercise Training and Habitual Physical Activity: A Randomized org/10.1002/oby.20145.
Controlled Trial. Am J Prev Med. 2012;43:629–35 Available from: http://www. 64. Donnelly JE, Hill JO, Jacobsen DJ, Potteiger J, Sullivan DK, Johnson SL, et al.
sciencedirect.com/science/article/pii/S0749379712006216. Effects of a 16-month randomized controlled exercise trial on body weight
and composition in young, overweight men and women: The midwest
44. Kozey-Keadle S, Libertine A, Lyden K, Staudenmayer J, Freedson PS.
exercise trial. Arch Intern Med. 2003;163:1343–50. https://doi.org/10.1001/
Validation of Wearable Monitors for Assessing Sedentary Behavior. Med Sci
archinte.163.11.1343.
Sport Exerc. 2011;43:1561–7.
65. Irving BA, Davis CK, Brock DW, et al. Effect of exercise training intensity on
45. Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo.
abdominal visceral fat and body composition. Med Sci Sports Exerc. 2009;
Endocr Rev. 1985;6:45–86.
40:1863–72.
46. Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De 66. R Core Team. R: A language and environment for statistical computing
Backer T, et al. Expert consensus document on the measurement of aortic
[Internet]. Vienna: R Foundation for Statistical Computing; 2018. Available
stiffness in daily practice using carotid-femoral pulse wave velocity. J
from: http://www.r-project.org/.
Hypertens. 2012;30:445–8.
47. Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA,
Cockcroft JR, et al. Recommendations for Improving and Standardizing Publisher’s Note
Vascular Research on Arterial Stiffness: A Scientific Statement from the Springer Nature remains neutral with regard to jurisdictional claims in
American Heart Association. Hypertension. 2015;66:698–722 Available published maps and institutional affiliations.
from: https://www.ahajournals.org/doi/full/10.1161/HYP.
0000000000000033?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_
dat=cr_pub%3dpubmed, DanaInfo.
48. David M, Malti O, AlGhatrif M, Wright J, Canepa M, Strait JB. Pulse Wave
Velocity Testing in the Baltimore Longitudinal Study of Aging. J Vis Exp.
2014;84:1–6.