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Both Traditional and Stair Climbing–based HIIT Cardiac Rehabilitation Induce Beneficial Muscle Adaptations

December 2020
Medicine and Science in Sports and Exercise Publish Ahead of Print(6)

December 2020
Publish Ahead of Print(6)

DOI:10.1249/MSS.0000000000002573

Authors:

Changhyun Lim

McMaster University

Emily C Dunford

McMaster University

Sydney Valentino

McMaster University

Sara Y Oikawa

McMaster University

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Purpose: There is a lack of knowledge as to how different exercise-based cardiac rehabilitation programming affects skeletal muscle adaptations in coronary artery disease (CAD) patients. We first characterized the skeletal muscle from adults with CAD compared to a group of age- and sex-matched healthy adults. We then determined the effects of a traditional moderate-intensity continuous exercise program (TRAD) or a high-intensity interval training program via stair climbing (STAIR) on skeletal muscle metabolism in CAD. Methods: Sixteen adults (n=16, 61±7 yrs), who had undergone recent treatment for CAD, were randomized to perform (3d/wk) either TRAD (n=7, 30 min at 60-80% of peak heart rate) or STAIR (n=9, 3x6 flights) for 12 wk. Muscle biopsies were collected at baseline in both CAD and healthy controls (n=9), and at 4 and 12 weeks after exercise training in CAD patients undertaking TRAD or STAIR. Results: We found that CAD had a lower capillary-to-fiber ratio (C/Fi, 35±25%, p=0.06), and capillary-to-fiber perimeter exchange (CFPE) index (23±29%, p=0.034) in type II fibers compared to healthy controls. However, 12wk of cardiac rehabilitation with either TRAD or STAIR increased C/Fi (type II, 23±14 %, p<0.001), and CFPE (type I, 10±23 %, p<0.01; type II, 18±22%, p=0.002). Conclusion: Cardiac rehabilitation via TRAD or STAIR exercise training improved the compromised skeletal muscle microvascular phenotype observed in CAD patients.

Baseline characteristics of the participants.

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Both Traditional and Stair Climbing–based HIIT Cardiac Rehabilitation

Induce Beneficial Muscle Adaptations

Changhyun Lim1, Emily C. Dunford1, Sydney E. Valentino1, Sara Y. Oikawa1,

Chris McGlory2, Steve K. Baker3, Maureen J. MacDonald1, Stuart M. Phillips1

1Department of Kinesiology, McMaster University, Hamilton, ON, Canada; 2School

of Kinesiology and Health Studies, Queens University, Kingston, ON, Canada;

3Department of Neurology, Michael G. DeGroote School of Medicine, McMaster

University, Hamilton, ON, Canada

Accepted for Publication: 18 November 2020

ACCEPTED

Both Traditional and Stair Climbing–based HIIT Cardiac Rehabilitation

Induce Beneficial Muscle Adaptations

Changhyun Lim1, Emily C. Dunford1, Sydney E. Valentino1, Sara Y. Oikawa1,

Chris McGlory2, Steve K. Baker3, Maureen J. MacDonald1, Stuart M. Phillips1

1Department of Kinesiology, McMaster University, Hamilton, ON, Canada, 2School

of Kinesiology and Health Studies, Queens University, Kingston, ON, Canada,

3Department of Neurology, Michael G. DeGroote School of Medicine, McMaster University,

Hamilton, ON, Canada

Corresponding author

Dr. Stuart M. Phillips

Professor, Department of Kinesiology, McMaster University,

1280 Main Street West, Hamilton, Ontario, Canada

Tel: +1 (905) 525-9140 ext. 24465

Email: phillis@mcmaster.ca

Medicine & Science in Sports & Exercise, Publish Ahead of Print

DOI: 10.1249/MSS.0000000000002573

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CL is supported by Basic Science Research Program through the National Research Foundation

of Korea (NRF) funded by the Ministry of Education (NRF-2019R1A6A3A03033939). SMP

thanks the Canada Research Chairs program. ECD was supported by the Canadian Institutes of

Health Research-Institute of Gender and Health grant. MJM and SMP are supported by Natural

Sciences and Engineering Research Council Discovery grant. Conflict of Interest. The authors

have no professional relationships with companies or manufacturers who will benefit from the

results of the present study. The results of the present study do not constitute endorsement by

ACSM. The authors declare that the results of the study are presented clearly, honestly, and without

fabrication, falsification, or inappropriate data manipulation.

ACCEPTED

Abstract

Purpose: There is a lack of knowledge as to how different exercise-based cardiac rehabilitation

programming affects skeletal muscle adaptations in coronary artery disease (CAD) patients. We

first characterized the skeletal muscle from adults with CAD compared to a group of age- and sex-

matched healthy adults. We then determined the effects of a traditional moderate-intensity

continuous exercise program (TRAD) or a high-intensity interval training program via stair

climbing (STAIR) on skeletal muscle metabolism in CAD. Methods: Sixteen adults (n=16, 61±7

yrs), who had undergone recent treatment for CAD, were randomized to perform (3d/wk) either

TRAD (n=7, 30 min at 60-80% of peak heart rate) or STAIR (n=9, 3x6 flights) for 12 wk. Muscle

biopsies were collected at baseline in both CAD and healthy controls (n=9), and at 4 and 12 weeks

after exercise training in CAD patients undertaking TRAD or STAIR. Results: We found that

CAD had a lower capillary-to-fiber ratio (C/Fi, 35±25%, p=0.06), and capillary-to-fiber perimeter

exchange (CFPE) index (23±29%, p=0.034) in type II fibers compared to healthy controls.

However, 12wk of cardiac rehabilitation with either TRAD or STAIR increased C/Fi (type II,

23±14 %, p<0.001), and CFPE (type I, 10±23 %, p<0.01; type II, 18±22%, p=0.002). Conclusion:

Cardiac rehabilitation via TRAD or STAIR exercise training improved the compromised skeletal

muscle microvascular phenotype observed in CAD patients.

Keywords

Coronary artery disease, stair climbing, high-intensity interval training, skeletal muscle

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Introduction

The global mortality rate resulting from cardiovascular disease (CVD) [including

coronary artery disease (CAD) and chronic heart failure (CHF)] is over 17 million persons

annually (1). Exercise-based cardiac rehabilitation is recommended to improve cardiovascular

function and quality of life, and reduce the risk of secondary CVD events (2). To date, most cardiac

rehabilitation exercise programs are designed for the improvement of cardiovascular function,

however, structural and functional abnormalities of skeletal muscle are also frequently observed

in CHF (3), and lower skeletal muscle mass has been associated with both low aerobic capacity

and increased mortality in CAD (4).

Microvascular circulation is essential for the maintenance of function in skeletal muscle

(5). Increases in blood flow and thereby shear stress promotes to the expression of pro-angiogenic

signals, especially endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor

(VEGF) protein (6). However, in CVD peripheral blood flow and oxygen perfusion is often

reduced due to cardiac dysfunction and poor vasoactive control (7, 8). Previous studies have shown

that patients with CAD and CHF have compromised skeletal muscle blood flow and diffusion of

oxygen (9, 10), lower mitochondrial density with reduced PGC 1α protein expression (11), and

unfavorable muscle fiber type distribution (12). Conversely, other studies have shown no

difference in measures of capillary density, mitochondrial volume and the enzymes related to

oxidative capacity with CHF (13, 14). Thus, there is conflicting evidence as to whether differences

in skeletal muscle phenotype exist between those with CVD and their healthy counterparts.

Critically, beyond CHF patients far less is known about the skeletal muscle characteristics in

individuals with CAD.

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Recent studies have reported that enhanced satellite cell activation and expansion are

related to greater skeletal muscle fiber capillarization in healthy young individuals (15), and that

capillarization is closely associated with skeletal muscle mass in older adults (16). To our

knowledge, no study has examined these skeletal muscle characteristics in individuals with CAD

compared to healthy controls. Further, little is known about how differing modes of cardiac-

rehabilitation exercise affect skeletal muscle characteristics in individuals with CAD.

Traditional exercise-based cardiac rehabilitation (TRAD) typically consists of moderate-

intensity aerobic exercise for at least 30 min per day, anywhere from 3-7 days a week (17).

Improvements in peak aerobic capacity as well as increased capillary density and succinate

dehydrogenase activity in skeletal muscle in CAD patients have been reported (10). High-intensity

interval exercise training (HIIT) has been shown to be a feasible and effective alternative to TRAD.

Currie et al. showed that three months and six months of stationary bicycle-based HIIT resulted in

equivalent improvements in cardiovascular function (V

O2peak and flow-mediated dilation) in CAD

patients compared to TRAD (18, 19). In addition, even one bout of HIIT demonstrated marked

improvements in the cardiovascular function highlighting the potency of HIIT as an exercise

stimulus to induce favorable physiological adaptations (20). However, less is known about skeletal

muscle adaptation in individuals with CAD following exercise-based cardiac rehabilitation.

The purpose of this study was twofold. First, we characterized differences in skeletal

muscle between individuals with CAD and age, body mass index (BMI), and sex matched healthy

participants. We hypothesized that, based on previous work in CHF patients, CAD participants

would have deteriorated skeletal muscle characteristics (number of satellite cells and capillary-

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related factors), and a relative fiber atrophy compared to healthy controls participants. We further

aimed to compare the effects of 12 weeks of TRAD and HIIT deployed as stair climbing exercise

training (STAIR) on skeletal muscle phenotype in individuals with CAD. We hypothesized that

both 12 weeks of TRAD and 12 weeks of STAIR would improve skeletal muscle characteristics

in individuals with CAD and that improvements would be similar between exercise modalities.

Methods

Ethics approval. All participants were informed of the purpose, experimental procedures and the

possible risks of the study before providing written informed consent. This study was approved by

the Hamilton Integrated Research Ethics Board (HIREB#3301) and conformed to the Declaration

of Helsinki. This study was registered as a clinical trial at clinicaltrials.gov (NCT03235674).

Participants reported on as part of this study were part of the larger research project (data reported

separately) examining the effectiveness of STAIR on improving endothelial function measured by

brachial artery flow-mediated dilation (FMD) in CAD patients completing outpatient cardiac

rehabilitation.

Participants. Twenty participants (18M/2F, 61±7 years) with CAD and who have had a history

of previous myocardial infarction, coronary artery bypass graft, and/or percutaneous coronary

intervention, were recruited for this study. A sample size calculation based on the primary outcome

variable of flow-mediated dilation showed that 13 participants per group would be adequate to

detect meaningful differences in that outcome. There was no specific sample size calculation

performed for the skeletal muscle characteristics.

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All participants were non-smokers, had stable medical therapy and had registered to

participate in exercise-based cardiac rehabilitation at the Cardiac Health and Rehabilitation Centre

(CHRC) at the Hamilton General Hospital. Exclusion criteria included any non-cardiac surgical

procedure within two months, symptomatic peripheral arterial disease that limits exercise capacity,

coronary heart failure (NYHA class II-IV confirmed via echocardiography), surgically inserted

pacemakers, atrial fibrillation, documented peak orifice area valve stenosis, any musculoskeletal

abnormality that would limit exercise participation (regular use of a mobility device,

neuromuscular or neurometabolic disease), unstable angina, uncontrolled hypertension (> 180/100

mmHg), and documented chronic obstructive pulmonary disease (FEV1 <60% and/or FVC <60%).

Two participants withdrew from the study due to time constraints. We were unable to collect

adequate muscle biopsy samples from two participants following the baseline biopsy; hence, total

16 participants (16M/1F, 61±7 years) were included in the analysis. In addition, we studied muscle

samples from nine healthy participants from previous trials the muscle from whom served as

controls, and were individually matched (according to age, sex, and BMI) with nine, randomly

selected, participants with CAD.

Study design. This study was a non-blinded, parallel group design. To examine differences in

resting skeletal muscle characteristics between CAD and healthy controls, muscle biopsies were

taken at baseline from the vastus lateralis for the determination of muscle fiber cross-sectional

area, satellite cell content, myonuclear content, capillary-related factors, and expression of proteins

related to vascular and mitochondrial function. Following screening assessments and baseline

measures, CAD participants were randomly assigned via a computer-generated random number

sequence, to participate in 12 weeks [6 supervised exercised sessions over 4 weeks, followed by 8

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weeks of unsupervised exercise (~24 exercise sessions)] of either TRAD or STAIR. Skeletal

muscle biopsies were taken at 4 weeks (following 6 supervised sessions) and after 8 additional

weeks (unsupervised session) of the exercise interventions in CAD participants only.

Rehabilitation exercise training. All participants performed a medically supervised

cardiopulmonary exercise test (CPET) on either a treadmill or cycle ergometer for the

measurement of peak cardiorespiratory fitness (V

O2peak), and peak heart rate (HRpeak) using

metabolic cart (Sensor Medics Vmax 229; California, USA) ahead of enrollment at the CHRC.

For the cycle ergometer, the workload was increased by 100 KPM per minute. For the treadmill,

the test was conducted in accordance with the Bruce protocol. The treadmill workload started at

2.0 mph with 0% grade and after one-minute, only the speed increased to 3.0 mph. Each minute

following, the incline increased by 2.5% grade. Once the grade reached 20%, the speed was

increased by 0.5mph per minute.

The TRAD training consisted of 30 min of moderate-intensity continuous exercise on

combination of stationary cycling, treadmill and/or self-paced walking The exercise intensity for

the TRAD group was determined using a target training heart rate from individual CPET results

through the heart rate-reserve (HRR) method. Exercise was completed at 60-80% HRRs with an

intensity goal of 11-13 on Borg’s Rate of Perceived Exertion (RPE) 6-20 scale. STAIR exercise

sessions consisted of 3 bouts of ascending and descending of single flight of stairs (12 steps) six

times at a self-selected vigorous intensity. Individuals in STAIR were asked to climb up and down

the stairs one step at a time and ascend at a pace that challenged them (RPE 14-15/20) and to

descend at a pace that was comfortable. Between each bout of stair climbing, participants

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performed 90 seconds of active recovery consisting of light walking on flat ground. Continuous

heart rate was monitored by a chest worn heart rate monitor (Polar A300, Polar H9 heart rate sensor,

Polar Electro Oy, Finland) to assess exercise intensity. Both TRAD and STAIR sessions began

with a 10 min warm-up and finished with a 5 min cool down consisting of light walking. To ensure

the use of proper technique, all participants performed 6 exercise sessions of their assigned

exercise modality at CHRC under the supervision of a certified healthcare professional for the first

4 weeks. For the subsequent 8 weeks, both groups were asked to continue to perform their exercise

program, unsupervised 3 days per week at home or in a community-based exercise facility.

Participants continued to use heart rate monitoring during at home exercise sessions and these data

were available to study investigators after upload by the participants.

Muscle biopsy procedure. All muscle biopsies were collected following an overnight fast (>10

hours) and were taken at baseline, and after 4 and 12 weeks of exercise training in CAD

participants, and at baseline only in healthy controls. Participants were advised to refrain from

exercise and alcohol consumption for 24 hours and caffeine consumption for 10 hours prior to

muscle biopsy sampling. All prescribed medications and vitamins were taken as usual, except for

any vasoactive medications (i.e., nitroglycerin). All muscle biopsies were obtained with the use of

a 5-mm Bergström needle that was adapted for manual suction under 1% xylocaine local

anesthesia. Muscle tissue was then carefully freed from visible connective tissue, fat, and blood

through manual dissection. A piece of the muscle tissue was embedded in optical cutting

temperature compound (OCT; Tissue-Tek, The Netherlands) for histochemical analysis and OCT

embedded tissue and whole muscle were both rapidly frozen in liquid nitrogen and stored at -80°C

for further analysis.

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Immunohistochemistry. Muscle tissue embedded in OCT was cut on a cryostat (5㎛) maintained

at a temperature of -20°C and transferred to a positively charged glass slide. After fixation in a 4%

paraformaldehyde (PFA) solution for 5 min, the slides were submerged in methanol and stored at

-20°C for 10 min to remove fat. After placement in a blocking solution (goat serum and 0.1%

triton/PBS at a 9:1 ratio) for 20 min, the slides were incubated with primary antibodies against

Pax7 (MAB 1675, 1:100, R&D system, Minneapolis, MN, USA), myosin heavy chain type I

(MHC I, A4.951, 1:1, Developmental Studies Hybridoma Bank, Iowa City, USA), myosin heavy

chain type II (MHC II, ab91506, 1:1000, Abcam, Cambridge, MA, USA), laminin (ab11575, 1:500,

Abcam, Cambridge, MA, USA), and CD31 (ab28364, 1:20, Abcam, Cambridge, MA, USA).

Secondary antibodies used for Pax 7 were (Alexa Fluor 594, 1:500, Thermo Fisher Scientific,

Waltham, MA, USA); MHC I (Alexa Fluor 488 or 594, 1:500, Thermo Fisher Scientific, Waltham,

MA, USA); MHC II (Alexa Fluor 647 or 350, 1:500, Thermo Fisher Scientific, Waltham, MA,

USA); laminin (Alexa Flour 488 or 350, 1:500, Thermo Fisher Scientific, Waltham, MA, USA);

CD31 (Alexa Flour 488, 1:500, Thermo Fisher Scientific, Waltham, MA, USA). Nuclei were

stained with 4,6-diamidino-2-phenylindole (DAPI, 1:20000, Sigma-Aldrich, Oakville, ON,

Canada). Lastly, the slides were mounted with Prolong Diamond Antifade Reagent (Life

Technologies, Burlington, ON, Canada). All analysis was completed with the investigator blinded

to group and time point.

Samples were imaged by Nikon Eclipse 90i microscope equipped with high-resolution

Photometrics CoolSNAP HQ2 fluorescence camera (Nikon Instruments, Melville, NY, USA). All

images were obtained with x 20 objective and analyzed using Nikon NIS element AR software

(Nikon Instruments). To ensure the reliability of cross sectional analysis (CSA), muscle fiber type,

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satellite cell content, and myonuclear content, ~200 muscle fibers per sample were analyzed (21).

Additionally, 50 muscle fibers per sample were analyzed for quantification of the capillary-to fiber

ratio on an individual fiber basis (C/Fi), and the capillary-to-fiber perimeter exchange index (CFPE)

for the measurement of capillary-to-fiber surface area (22).

Western blotting. To analyze protein expression and phosphorylation, snap-frozen muscle tissue

was homogenized with ice-cold lysis buffer [10μL/mg; 25mM Tris 0.5% vol: vol Triton X-100

and protease/phosphatase inhibitor cocktail tablets (Complete Protease inhibitor Mini-Tabs, Roche;

and PhosSTOP, Roche Applied Science)] and centrifuged at 1,500 g for 10 min at 4°C. The protein

concentration of the supernatant (sarcoplasmic fraction) was determined via bicinchoninic acid

assay (Thermo Scientific, Waltham, MA, USA). 4X Laemmli buffer (0.25 M Tris, 4% SDS, 20%

glycerol, 0.015% bromophenol blue and 10% 2-mercaptoethanol) was added to working samples

and equal amounts of protein (10 ㎍) from each sample were loaded into wells on 4-15% TGX

Stain-Free Precast Gels (Bio-Rad, Hercules, CA, USA). A protein ladder (Precision Plus Protein

Standard, Bio-Rad, Hercules, CA, USA) and 4 internal standard calibration curves were loaded on

every gel. Gel electrophoresis was run at 200 volts for 45 min. The protein transfer from the gel to

a nitrocellulose membrane was carried out by turbo transfer (#1704150, Bio-Rad, Hercules, CA,

USA). To ensure a complete protein transfer, membrane pre- and post-transfer images were

checked using the ChemiDoc MP Imaging System (#12003154, Bio-Rad, Hercules, CA, USA).

Membranes were then blocked with 5% bovine serum albumin (BSA) for 90 min at room

temperature. The primary antibodies, total endothelial nitric oxide synthase (eNOS, 9572, 1:1000,

Cell signaling, Danvers, MA, USA), phospho-eNOSSer1177 (9571S, 1:1000, Cell signaling, Danvers,

MA, USA), vascular endothelial growth factor (VEGF, ab46154, 1:1000, Abcam Cambridge, MA,

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USA), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-alpha,

Ab3242, 1:1000, Merck Millipore, Billerica, MA, USA), cytochrome c oxidase subunit IV (COX

IV, Ab110261, 1:1000, Abcam, Cambridge, MA, USA) were incubated in a blocking solution for

12 hours at 4°C. The membranes were then washed 3 x 5 min with tris-buffered saline and Tween

20 (TBS-T, Millipore Sigma, Oakville, ON, Canada), and incubated with the appropriate host

species secondary antibody for 90 min at room temperature. The secondary antibodies were

removed by 3 x 5 min washing with TBS-T. Membrane bands were detected by

chemiluminescence solution (Clarity Western ECL substrate, Bio-Rad, Hercules, CA, USA) and

images were scanned using the ChemiDoc MP Imaging system, and analyzed by Image Lab

Software for PC version 6.0.1.

Statistical analysis. The distribution of data was assessed using the Shapiro-Wilk test. All non-

normally distributed data are specified in the figure legend. Characteristics of CAD and healthy

control participants, and TRAD vs. STAIR participants at baseline, were analyzed with an

independent sample t-test, for normally distributed data, or a Mann-Whitney test for non-normally

distributed data. Two-way repeated measures analysis of variance (ANOVA) was used to compare

TRAD and STAIR with the exercise intervention as the between-subjects variable and time

(Baseline, 4 weeks and 12 weeks) as the within-subjects variable. All significant interactions from

the ANOVA analysis were further examined via Tukey’s post hoc test. Differences in non-normal

distributed data in this comparison were analyzed with robust two-way between-within ANOVA

in R. Trimmed means were used as a measure of location rather than the mean, which is subject to

outlier effects, with the trimming parameter set to 0.2. Hochberg-adjusted multiple comparisons

for interaction and main effects were conducted using the ‘bwmcppb.adj’ function to control for

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familywise error, as described in Wilcox (23). Statistical significance was set at p < 0.05. Data are

presented as means±SD or graphed as means with individual data and showing the 95% confidence

interval (CI). Statistical analyses were completed using the SPSS Statistics software package

(SPSS Statistics, Version 26.0 for Windows, IBM Corp., Armonk, NY, USA) or R (version 4.0.2).

Results

Participant Characteristics. Baseline characteristics of the participants are presented in Table 1.

There were no differences in anthropometric measures between CAD and healthy controls

(p>0.05), or between TRAD and STAIR (p>0.05). There were no differences in clinical outcomes,

aerobic fitness (V

O2peak), CVD risk factors (type 2 diabetes, hypertension, dyslipidemia), blood

variables (fasted glucose, fasted insulin, high-density lipoprotein, low-density lipoprotein,

Triglycerides, cholesterol), or medication between TRAD and STAIR (p>0.05).

Characteristics of cardiac rehabilitation exercise. Participants in both the TRAD (3.0±2.2

d/week) and STAIR (3.0±3.2 d/week) groups adhered to their respective exercise programs

throughout the 12 weeks intervention. During exercise, STAIR elicited a greater HRpeak compared

to TRAD (112±14 vs 129±11 bpm, p=0.008). In addition, the average %HRpeak was 12% higher

in STAIR compared to TRAD (p=0.028). The average total exercise time per session at the

prescribed intensity of STAIR was significantly shorter compared to TRAD (STAIR: 5±2 min

versus TRAD: 33±8 min, p<0.001). Exercise protocol values following 12 weeks of exercise

training are presented in Supplemental Digital Content 1, http://links.lww.com/MSS/C212.

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Skeletal muscle phenotype in CAD and healthy controls. Participants with CAD had a 52±88%

lower prevalence of type I fibers (p=0.034) and 14±21% higher percentage of type II fibers

(p=0.034) (Figure 1A). There were no differences in fiber CSA for type I or II fibers between CAD

and healthy controls (type I fibers: p=0.141, type II fibers: p=0.084, Figure 2B). There was no

difference in satellite cell (p=0.282) or myocnulei content per fiber in type II fibers between CAD

and healthy controls (p=0.094), however, type I muscle fiber-associated satellite cell and

myonuclei content per fiber were 181±354% (p=0.019) and 24±22% (p=0.017) lower in CAD

compared to healthy controls respectively (Figure 1C and D). There were no differences in C/Fi

number (p=0.063) or CFPE index (p=0.123) in type I fibers between CAD and healthy controls.

However, type II fiber C/Fi number and CFPE index were 35±25% (p=0.06) and 23±29% (p=0.034)

lower in CAD compared to healthy controls respectively (Figure 1E and F).

Capillary and mitochondria-related protein expression between CAD and healthy controls.

There was no difference in the ratio of phosphorylation to total eNOSSer1177 (p=0.24) or COX IV

(p=0.44) protein expression between CAD and healthy controls (Figure 2A and D). PCG 1α and

VEGF protein expression in CAD was 128±149% (p=0.024) and 120±173% (p=0.044),

respectively lower compared to healthy controls (Figure 2B and C).

Changes in skeletal muscle phenotype with exercise training in CAD patients. There were no

changes in fiber CSA during the exercise training interventions (type I fibers: p=0.39, type II fibers:

p=0.911) and no differences between CAD groups (type I fibers: p=0.67, type II fibers: p=0.638)

at any time point (Figures 3A and B). Satellite cell content per fiber in type I fibers increased at 4

weeks (22±56%, p=0.011) with no difference between training groups (p=0.076). Satellite cell

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content per fiber in type I fibers returned to those similar to baseline at 12 weeks (p=0.284, Figure

3C). Satellite cell content per fiber in type II fibers was greater at 12 weeks of training compared

to baseline (35±35%, p=0.046) and at 4 weeks (25±33%, p=0.003) in STAIR only (Figure 3D).

There was no difference in the number of myonuclei per fiber at 4 weeks (type I fibers: p=0.406,

type II fibers: p=0.05); however, myonuclei number per fiber increased by 8±15% in type I fibers

(p=0.012) and 12±19% in type II fibers (p=0.006) following 12 weeks of training with no

differences between groups (type I fibers: p=0.359, type II fibers: p=0.952) (Figure 3E and F).

Capillarization with exercise training in CAD patients. There was no difference in C/Fi number

in type I fibers following TRAD or STAIR training at any timepoint (p>0.05, Figure 4A). C/Fi in

type II fibers increased by 17±12at 4 weeks (p<0.001) and by 23±14 at 12 weeks (p<0.001) with

no difference between groups (p=0.30) (Figure 4B). CFPE index in type I fibers increased by

11±14% at 4 weeks (p<0.01) and by 10±23% at 12 weeks (p<0.01) with no difference between

groups (p=0.066) (Figure 4C). CFPE index increased 18±14% at 4 weeks (p<0.001) and 18±22%

at 12 weeks (p=0.002) in type II fibers with no difference between groups (p=0.17) (Figure 4D).

Capillary and mitochondria-related protein expression with exercise training in CAD

patients. There was a significant increase in the ratio of phosphorylation to total eNOSSer1177 at 4

weeks of training by 19±33% (p<0.01) with no difference between groups (p=0.127). This ratio

was not change from baseline at 12 weeks (p=0.073, Figure 5A). There was no difference in VEGF

protein expression at 4 weeks or 12 weeks (p>0.05, Figure 5B). Protein expression of PGC 1α

increased by 19±52% at 4 weeks (p=0.046) and 23±41% at 12 weeks (p=0.014) with no differences

between groups (p=0.11) (Figure 5C). There was a main effect for time in protein expression of

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COX IV (p=0.048). However, there was no significant post-hoc effect when p-values are adjusted

for multiple comparisons (Figure 5D).

Discussion

We discovered marked differences in skeletal muscle characteristics in CAD patients compared to

age, sex, and BMI-matched healthy older adults as evidenced by a lower percentage of type I fibers,

a decreased number of satellite cells, and decreased number of myonuclei per fiber in type I fibers.

Additionally, skeletal muscle from CAD patients exhibited significantly reduced capillary-related

indices C/Fi and CFPE in type II fibers, as well as lower VEGF and PGC1α protein expression

compared to controls. We are uncertain whether these findings are a determinant or consequence

of CAD, but they highlight that CAD patients have a lower skeletal muscle metabolic quality and

display a pre-sarcopenic skeletal muscle phenotype (24). Critically, we show for the first time, to

our knowledge, that despite reduced satellite cell and myonuclear content, and lower capillary-

related factors compared to healthy controls, individuals with CAD are able to ameliorate these

decrements with 12 weeks of either TRAD or STAIR exercise training. Additionally, despite a 6-

fold shorter average exercise time required by STAIR (~5±2 min) versus TRAD (~33±8 min), we

observed comparable changes in skeletal muscle phenotype with training. Interestingly, we did

observe increased satellite cell proliferation in type II fibers to a greater extent following the

STAIR program, which is deserving of follow-up.

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Skeletal muscle characteristics in individuals with CAD

In general, aging results in the atrophy of type II fibers along with a reduction in the

number of satellite cells and myonuclei per fiber (25). We could not detect differences in the

number of type II fiber satellite cells and myonuclei per fiber between CAD and healthy

participants; however, CAD participants exhibited a lower number of satellite cells and myonuclei

in type I fibers compared to healthy participants. Satellite cells play a vital role in skeletal muscle

repair, remodeling, and growth (26). In aging muscle, declines in satellite cell content are

associated with type II fiber atrophy, which includes loss of muscle mass as well as a loss of the

total number of muscle fibers due to denervation (27). We note that CHF patients have

compromised mitochondrial and capillary-related phenotypes but we could not find an

investigation examining satellite cell characteristics in CHF or CAD patients (28); hence, our data

in CAD patients are a first and without an easy CVD-related comparison. Therefore, while the

profile of type II fibers in CAD was in line with what would be expected with a natural sarcopenic

decline (Figure 1), the presence of CAD is associated with a type I fiber-specific deterioration in

aging skeletal muscle (Figure 1).

Muscle perfusion can have substantial impacts on substrate delivery and many cellular

processes such as protein turnover (5) and oxygen delivery (29). We observed that C/Fi and CFPE

in type II fibers in CAD were lower compared to healthy controls. Additionally, VEGF, an

angiogenic growth factor, showed significantly lower protein expression in CAD participants

compared to healthy controls, findings that are line with the observed reduction in C/Fi in CAD;

however, there was no difference in eNOS protein expression between CAD patients and healthy

controls (Figure 2A and B). We also found that type II fibers in the skeletal muscle of CAD

ACCEPTED

participants had a lower CFPE index compared with healthy controls. Hepple et al., reported a

positive correlation between V

O2peak and CFPE index (30) which supports the notion that impaired

oxygen delivery to skeletal muscle in CAD patients may be due to reduced capillarization in their

skeletal muscle. Previous studies have reported increases in the ubiquitin-proteasome system

through increases in ubiquitin ligases, MuRF1 and MAFbx in CHF patients (31), and decreased

mitochondria content by reduced PGC 1α protein expression in CVD (11). In the present study,

besides PGC 1α protein expression which was lower in CAD, there were no differences in the

CSA of type I or II fibers or differences in the protein expression of COX IV in CAD participants

compared to healthy controls. Further studies are required to fully elucidate the mechanisms

resulting in altered skeletal muscle phenotypes in CAD patients.

Cardiac rehabilitation and skeletal muscle adaptation in CAD patients

To our knowledge, there are very few studies examining the impact of cardiac

rehabilitation on skeletal muscle metabolism in individuals with CAD (4, 10), with no study that

has investigated the effects on skeletal muscle fiber type adaptations. Following 12 weeks of

training, there were no differences in the CSA of type I or II fibers in either group; however, 4

weeks of both TRAD and STAIR was associated with an increase in the number of satellite cells

in type I fibers. Satellite cells are robustly activated in earlier phases of exercise training an effect

that may not be due to muscle damage but may be a normal part of phenotypic adaptation (32).

While there were no differences in the change in satellite cell number in type I fibers between

groups, 12 weeks of STAIR increased satellite cell content in type II fibers to a greater extent

compared to TRAD. Previous studies indicated that HIIT may induce a greater increase in satellite

cell content, particularly in type II fibers versus moderate-intensity endurance exercise (33, 34). In

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line with these observations, the higher intensity nature of STAIR may have increased the

recruitment of type II fibers in comparison to TRAD, resulting in the greater satellite cell content

in type II fibers at the 12 week timepoint (35). Satellite cell-mediated myonuclear accretion is a

hallmark of largely with skeletal muscle hypertrophy when the upper limits of the myonuclear

domain are reached (36). However, previous studies have shown that satellite cell-mediated

myonuclear accretion can occur with non-hypertrophic stimuli, including endurance exercise, and

may contribute to remodeling of muscle fibers (32).

Both endurance exercise (37) and resistance exercise (38) can promote the expression of

angiogenesis-related signals by including an increase in blood flow and thereby shear stress (6).

Indeed, Tan et al. reported that 6 weeks of HIIT using a cycle ergometer increased capillary

contacts (CC) in type I and II fibers in overweight women (39), and Cocks et al. also reported

increased muscle microvascular eNOS content and capillarization following 6 weeks sprint

interval training and traditional endurance training (40). We report that 4 weeks of both TRAD

and STAIR increased C/Fi in type II fibers in CAD participants and that increase was maintained

at 12 weeks of training in both groups. This finding is paralleled by the observed increase in

maximal V

O2peak following training [Dunford and MacDonald, personal communication]. As

increased capillary density is not only closely connected to the delivery of oxygen and nutrients

but also enhances activation and expansion of satellite cell content for skeletal muscle repair (15);

thus, the increased capillary density following TRAD and STAIR may allow for regeneration and

repair of comprised skeletal muscle in CAD. Indeed, individuals who have a lower capillarization

in skeletal muscle at baseline showed the lower extent of skeletal muscle mass increase following

resistance exercise in older men (16), and 12 months of longer exercise-based traditional cardiac

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rehabilitation increased individual fiber area accompanied with increased capillary density in CAD

patients (10). While Tan et al. reported the increase in CC for both type I and II fibers following

HIIT (39), we observed the increase in C/Fi in type II fibers only. The disparate findings may be

due to the characteristics of different participants performing the exercise training.

Secretion of VEGF protein during exercise plays critical roles in promoting angiogenesis

by stimulating endothelial cells to proliferate, migrate, and differentiate (41). In addition, VEGF

upregulates the expression of eNOS, which synthesizes endothelial nitric oxide (NO) (42). The

release of endothelial NO induces vasodilation and thereby improves blood flow and perfusion

(43). We observed no further increase in C/Fi at 12 weeks of both TRAD and STAIR from 4 weeks

(Figure 4). In line with our observations, 4 weeks of both TRAD and STAIR increased

phosphorylation of eNOS but these values returned to those similar to baseline at 12 weeks.

However, there were no changes in VEGF protein expression in either group following exercise

training despite an increased C/Fi. An increase in VEGF protein expression following exercise is

transient, with levels returning to baseline within 2 hours after exercise cessation (44). Given that

muscle biopsies were collected at rest and participants were required to refrain from physical

activity 24 hours prior to muscle biopsy sampling, the lack of augmented VEGF is perhaps not

surprising.

Individuals with CHF had reduced oxidative capacity of skeletal muscle indicative of

lower mitochondria density (9). Here we show that both TRAD and STAIR increased expression

of the PGC 1α after 4 and 12 weeks, whereas there was no difference in protein expression of COX

IV following either exercise training program (45). Six sessions of HIIT over 2 weeks led to the

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increase in mitochondria content measured by citrate synthase (CS) activity and respiration in

young men (46). In addition, 6 weeks of HIIT increased mitochondrial content in older men and

women (47). Given that the former study, while the 2 weeks of HIIT training duration was possible

to induce mitochondrial biogenesis in young adults, CAD patients who have relatively

compromised skeletal muscle characteristics may need a longer period of training to lead to

mitochondrial biogenesis even though the expression of PGC 1α was increased at 4 and 12 weeks

of training. Mitochondrial volume and content have been correlated with V

O2peak (48), which is a

strong predictor of mortality (49), and CAD patients generally have a lower oxygen consumption

capacity. Thus, exercise training following a cardiac event should be considered as a means to

improve muscle oxidative capacity in CAD individuals.

Our novel findings highlight that while CAD patients have compromised skeletal muscle

function compared with healthy controls, that both TRAD, and a practical and time-efficient

alternative, STAIR, are equally effective in improving skeletal muscle metabolic characteristics

following a cardiac event. However, we recognize that our small sample size is a limitation as this

would inflate the risk of a type II statistical error. Also, 8 weeks of the training was unsupervised,

so we were not able to control the exact exercise intensity performed by participants and had to

rely on self-report and heart rate monitoring results for adherence estimates and confirmation.

In conclusion, we show that CAD is associated with smaller muscle fibers, reductions in

satellite cell and myonuclei number, and capillary-related perfusion capacity of skeletal muscle in

comparison to healthy controls. Critically, we found that 4 and 12 weeks of cardiac rehabilitation

in the form of either TRAD or STAIR improved these compromised skeletal muscle characteristics

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by increasing the number of satellite cells, myonuceli, and capillary-related factors induced by

CAD. We conclude that skeletal muscle metabolism in individuals with CAD can be improved

with exercise-based cardiac rehabilitation. Also, HIIT-based stair climbing, which is easily

accessible, could be a feasible and practical alternative to traditional cardiac rehabilitation exercise,

despite shorter average exercise time.

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Acknowledgments

CL is supported by Basic Science Research Program through the National Research Foundation

of Korea (NRF) funded by the Ministry of Education (NRF-2019R1A6A3A03033939). SMP

thanks the Canada Research Chairs program. ECD was supported by the Canadian Institutes of

Health Research-Institute of Gender and Health grant. MJM and SMP are supported by Natural

Sciences and Engineering Research Council Discovery grant.

Conflict of Interest

The authors have no professional relationships with companies or manufacturers who will benefit

from the results of the present study. The results of the present study do not constitute endorsement

by ACSM. The authors declare that the results of the study are presented clearly, honestly, and

without fabrication, falsification, or inappropriate data manipulation.

ACCEPTED

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Figure legends

Figure 1. Skeletal muscle characteristics in CAD patients and healthy controls. The ratio of

the fiber type composition to type I and type II (A) and the cross-sectional area (B). The number

of Pax7+ satellite cells (C) and myonuclei (D) per fiber. Individual muscle fiber capillary-to-fiber

ratio (C/Fi) (E) and capillary-to-fiber perimeter exchange (CFPE) per 1000㎛ of cross-sectional

area (F). CAD: coronary artery disease, white bars represent healthy controls, grey bars represent

CAD, Data are expressed as means and 95% CI±SD. *p<0.05, significantly different from healthy

controls within each fiber type.

Figure 2. Expression of capillary and mitochondria-related proteins. The ratio of

phosphorylation to total endothelial nitric oxide synthase (eNOS)Ser1177 (A), vascular endothelial

growth factor (VEGF) (B), peroxisome proliferator-activated receptor-gamma coactivator 1α

(PGC 1α) (C; Mann-Whitney test), and cytochrome c oxidase subunit IV (COX IV) (D; Mann-

Whitney test), representative western blotting bands (E). AU: arbitrary unit, HC: healthy controls,

CAD: coronary artery disease, white bars represent TRAD, grey bars represent STAIR. Data are

expressed as means and 95% CI. *p<0.05, significantly different from healthy controls.

Figure 3. Changes in skeletal muscle characteristics at 4 and 12 weeks following TRAD and

STAIR training in CAD patients. Skeletal muscle CSA for type I (A; Robust ANOVA) and type

II (B). The number of Pax7+ satellite cells per fiber for type I (C) and type II (D). The number of

myonuclei per fiber for type I (E) and type II (F). CSA: cross-sectional area, BL: baseline, 4w: 4

weeks, 12w: 12 weeks, TRAD: traditional moderate-intensity continuous exercise program,

STAIR: stair climbing based high-intensity interval exercise program, white bars represent TRAD,

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grey bars represent STAIR, Data are expressed as means and 95% CI. *p<0.05, significantly

different from BL within group, # p<0.05, significantly different from 4w within group, † p<0.05

significantly different from BL.

Figure 4. Changes in capillarization at 4 and 12 weeks following TRAD and STAIR training

in CAD patients. Individual muscle fiber capillary-to fiber ratio (C/Fi) for type I (A) and type II

(B; Robust ANOVA). Capillary to fiber perimeter exchange (CFPE) per 1000㎛ for type I (C;

Robust ANOVA) and type II (D). BL: baseline, 4w: 4 weeks, 12w: 12 weeks, TRAD: traditional

moderate-intensity continuous exercise program, STAIR: stair climbing based high-intensity

interval exercise program, white bars represent TRAD, grey bars represent STAIR. Data are

expressed as means and 95% CI. † p<0.05, significantly different from BL.

Figure 5. Changes in expression of capillary and mitochondria-related proteins at 4 and 12

weeks following TRAD and STAIR training in CAD patients. The ratio of phosphorylation to

total endothelial nitric oxide synthase (eNOS)Ser1177 (A; Robust ANOVA), vascular endothelial

growth factor (VEGF) (B), peroxisome proliferator-activated receptor-gamma coactivator 1α

(PGC 1α) (C), and cytochrome c oxidase subunit IV (COX IV) (D; Robust ANOVA),

representative western blotting bands (E). AU: arbitrary unit, BL: baseline, 4w: 4 weeks, 12w: 12

weeks, TRAD: traditional moderate-intensity continuous exercise program, STAIR: stair climbing

based high-intensity interval exercise program, white bars represent TRAD, grey bars represent

STAIR. Data are expressed as means and 95% CI. †p<0.05, significantly different from BL.

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Supplemental Digital Content

Supplemental Digital Content 1. Table 1 that illustrate the exercise protocol values following 12

weeks of exercise training. doc.

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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Figure 5

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Table 1. Baseline characteristics of the participants.

Variables

Healthy

Controls (n=9)

CAD (n=9)

CAD (n=16)

TRAD (n=7)

STAIR (n=9)

Sex (M/F)

(9/0)

(7/0)

(8/1)

Age (years)

66±4

64±5

61 ± 10

62 ± 6

Height (cm)

175±6

173±5

174 ± 3

175 ± 6

Body mass (Kg)

91±14

90±12

97 ± 20

90 ± 11

BMI (kg/m2)

30±4

30.2 ± 3.7

29.8 ± 3.3

VO2peak (L/kg/min)

21.7±3.9

23.2±2.5

21.4±4.5

Clinical

STEMI n (%)

3 (33.3)

1 (14.3)

2 (22.2)

NSTEMI n (%)

4 (44.4)

4 (57.1)

5 (55.6)

Angina n (%)

1 (11.1)

1 (14.3)

2 (22.2)

PCI n (%)

6 (66.7)

4 (57.1)

7 (77.8)

CABG n (%)

3 (33.3)

3 (42.9)

2 (22.2)

Time since event (weeks)

9±6

8±4

9±5

Medications

Beta-blockers n (%)

6 (85.7)

9 (100)

ACE inhibitors n (%)

6 (85.7)

6 (66.6)

ASA n (%)

7 (100)

9 (100)

Lipid lowering n (%)

7 (100)

9 (100)

Metformin n (%)

1 (14.3)

1 (11.1)

CVD risk factors

T2DM n (%)

3 (33.3)

2 (28.6)

1 (11.1)

Hypertension n (%)

6 (66.6)

6 (85.7)

6 (66.7)

Dyslipidemia n (%)

6 (66.6)

6 (85.7)

6 (66.7)

Blood markers

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Fasted glucose (mM/L)

5.6±1.0

5.4±1.0

5.8±1.00

Fasted insulin (mIU/L)

10.1±6.7

7.3±2.3

12.8±6.8

HDL (mM/L)

1.0±0.3

1.1±0.4

1.0±0.4

LDL (mM/L)

1.3±0.4

1.4±0.4

Triglycerides (mM/L)

1.0±0.4

0.8±0.2

1.1±0.4

Cholesterol (mM/L)

2.7±0.6

2.7±0.8

2.9±0.7

Data are expressed as means±SD. BMI: body mass index, STEMI: ST-elevation myocardial

infarction, NSTEMI: non-ST-elevation myocardial infarction, PCI: percutaneous intervention,

CABG: coronary artery bypass graft, ACE: angiotensin-converting enzyme, ASA: acetylsalicylic

acid, T2DM: type 2 diabetes mellitus, HDL: high-density lipoprotein, LDL: low-density

lipoprotein, CAD: coronary artery disease. TRAD: traditional moderate-intensity continuous

exercise program, STAIR: stair climbing based high-intensity exercise program.

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Supplemental Digital Content

Supplemental Digital Content 1. Table 1 that illustrate the exercise protocol values following 12

weeks of exercise training. doc.

Table 1. Exercise protocol values following 12 weeks of exercise training.

TRAD (n=7)

STAIR (n=9)

HRpeak (bpm)

112±14

129±11*

0.008

%HRpeak

89±5

101±1*

0.028

Average of total exercise time

at prescribed intensity (min)

33.3±8.1

5.2±2.2*

<0.001

Data are expressed as means±SD. HR: heart rate, TRAD: traditional moderate-intensity

continuous exercise program, STAIR: stair climbing based high-intensity interval exercise

program. * p<0.05 significantly different from TRAD.

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Effect of Short Bouts of Vigorous Stair Climbing on Cardiorespiratory Fitness in Overweight or Obese Women: A Pilot Feasibility Study

Article

Nov 2023

Background: We examined the effect of 4 weeks of a brief vigorous stair climbing exercise on cardiorespiratory fitness (CRF) and body composition in women with overweight or obesity. Methods: Twenty-six participants (age, 25.4±4.9 years; body mass index [BMI], 25.3±1.8 kg/m2) were randomly assigned to either a stair climbing exercise group (n=13) or a non-exercising control group (n=13). The stair climbing exercise group performed 20 sessions (supervised, five sessions/week over 4 weeks) of brief intermittent stair climbing exercise consisting of a 3-minute warm-up followed by three bouts of 20 seconds of stair climbing (≥80% of age-predicted maximum heart rate) interspersed with 2-minute recovery periods (total exercise duration=10 minutes/session). Peak oxygen uptake (VO2peak) was measured using a graded maximal treadmill test with the use of a standard open-circuit spirometry technique. Body composition was assessed with bioelectrical impedance analysis. Results: All participants, except one who dropped out due to coronavirus disease 2019 (COVID-19) infection, completed the study with 100% attendance rates. There were significant interaction effects (group×time) on body weight, BMI, waist circumference, and CRF such that the stair climbing exercise group had significant (P≤0.01) reductions in body weight (66.5±4.6 to 65.2±4.6 kg), BMI (24.8±1.2 to 24.4±1.1 kg/m2), and waist circumference (78.0±3.7 to 76.5±4.1 cm) and improvements in VO2peak (31.6±2.5 to 34.9±2.6 mL/kg/min) compared with controls. Conclusion: Short bouts of vigorous stair climbing is a feasible and time-efficient exercise strategy for improving CRF in previously sedentary, young women with overweight and obesity.

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Full-text available

Dec 2023

Introduction Hypertrophy is the process of increasing the mass of a tissue. In this article, we focused on the impact of the mechanisms of muscle hypertrophy, its effect on the human body, correlation with the course of diseases and tolerance of treatment. We considered the benefits of having well-developed, and also touched on the problems of underdeveloped muscle mass. Results The main factors causing hypertrophy are resistance exercise training, mechanotransduction, metabolic pathways, ribosomal biogenesis, gene expression and the impact of hormones. The beneficial effect of high concentrations of testosterone and growth hormone, also IGF1, on skeletal muscle hypertrophy has been proven. On the other side, the studies have shown that high concentrations of glucocorticoids, such as cortisol are associated with reduced muscle mass. There are many positive aspects of a well-developed muscle mass such as an impact on the prognosis in patients with cancers and sometimes reduces mortality among them. The problems of low muscle mass and sarcopenia are also mentioned. Low muscle mass can affect the poor prognosis of diseases such as cancer, hepatic cirrhosis and COVID-19. Postoperative complications are more common in patients with low muscle mass. One way to prevent this process may be to introduce resistance exercise training in patients struggling with problems of muscular atrophy. Conclusion Skeletal muscles have multiple functions in the human body. In addition to movement, they play a role in molecular processes like hormonal regulation. In addition, they can, when well developed, positively influence healing processes and the course of disease.

An Evidence-Based Narrative Review of Mechanisms of Resistance Exercise-Induced Human Skeletal Muscle Hypertrophy

Article

Full-text available

Apr 2022

Skeletal muscle plays a critical role in physical function and metabolic health. Muscle is a highly adaptable tissue that responds to resistance exercise (RE; loading) by hypertrophying or, during muscle disuse, RE mitigates muscle loss. Resistance exercise training (RET)-induced skeletal muscle hypertrophy is a product of external (e.g., resistance exercise programming, diet, some supplements) and internal variables (e.g., mechano-transduction, ribosomes, gene expression, satellite cells activity). Resistance exercise is undeniably the most potent non-pharmacological external variable to stimulate the activation/suppression of internal variables linked to muscular hypertrophy or countering disuse-induced muscle loss. Here, we posit that despite considerable research on the impact of external variables on RET and hypertrophy, internal variables (i.e., inherent skeletal muscle biology) are dominant in regulating the extent of hypertrophy in response to external stimuli. Thus, identifying the key internal skeletal muscle-derived variables that mediate the translation of external resistance exercise variables will be pivotal to determining the most effective strategies for skeletal muscle hypertrophy in healthy persons. Such work will aid in enhancing function in clinical populations, slowing functional decline, and promoting physical mobility. We provide up-to-date, evidence-based perspectives of the mechanisms regulating RET-induced skeletal muscle hypertrophy.

Exercise Snacks: A Novel Strategy to Improve Cardiometabolic Health

Article

Oct 2021

We define exercise snacks as isolated ≤1-minute bouts of vigorous exercise performed periodically throughout the day. We hypothesize that exercise snacks are a feasible, well-tolerated and time-efficient approach to improve cardiorespiratory fitness and reduce the negative impact of sedentary behaviour on cardiometabolic health. Efficacy has been demonstrated in small proof-of-concept studies. Additional research should investigate this novel physical activity strategy.

Stair-climbing interventions on cardio-metabolic outcomes in adults: A scoping review

Article

Full-text available

Nov 2023

Objective Physical inactivity is linked with high chronic disease risk; however, only a fraction of the global population meets the recommendations for physical activity. Stair-climbing is a simple and accessible form of physical activity that has been shown to improve cardio-metabolic outcomes in adults. The present scoping review explores the physiological and therapeutic effects of stair-climbing interventions on adult cardio-metabolic disease risk factors. Methods This scoping review followed the reporting guidelines of the Arksey & O'Malley framework, which collates evidence in stages. The research question was framed as “What are the effects of stair climbing on cardio-metabolic outcomes in adults?”. Eligible articles were identified through an extensive search of four electronic databases, and data from 24 research studies were charted and organized. Results Stair climbing improves aerobic capacity (8–33 ml kg/min) and serum biomarkers by ≈9–15 %. A minimum of 4–8 weeks are necessary to alter cardiometabolic risk. Regular stair climbing can improve cardio-metabolic risk indicators, including body composition, blood pressure, cholesterol levels, and insulin sensitivity. The research regarding inflammatory and musculoskeletal changes with stair climbing bouts is still in its infancy. Conclusion Stair climbing interventions are a no-cost and feasible form of physical activity for improving cardiometabolic disease risk in adults.

Differences in Skeletal Muscle Fiber Characteristics Between Affected and Nonaffected Limbs in Individuals With Stroke: A Scoping Review

Article

Jul 2023
PHYS THER

Objective: The objective of this scoping review was to characterize and identify knowledge gaps about the changes in skeletal muscle fiber type proportion and cross-sectional area (CSA) after stroke. Methods: This scoping review followed previously proposed frameworks. A systematic search was conducted for articles examining muscle fiber type proportion and CSA in individuals with stroke in EMBASE, MEDLINE, PsycINFO, CINAHL, SPORTDiscus, and Web of Science databases from inception to December 20, 2022. Two independent authors screened and extracted data. Results were discussed using theories proposed by the authors of the included studies. Results: Of 13 studies (115 participants), 6 (46%) were case studies or case series, 6 (46%) were cross-sectional studies, and 1 (8%) was an experimental study. Studies had small sample sizes (1-23 participants) and various muscle sampling sites (6 different muscles). All 13 studies examined muscle fiber type distributions, and 6 (46%) examined CSA. Ten (77%) studies examined differences between paretic and nonparetic muscles and 5 (38%) compared people with stroke to people without stroke. Results from 9 of 13 studies (69%) supported a greater proportion of type II fibers in the paretic limb. Of those, 4 studies (42 participants), 3 studies (17 participants), and 1 study (1 participant) saw no differences in preferential type II and type I CSA loss between limbs. Conclusions: Of the limited available evidence, stroke appears to result in a shift to a higher proportion of type II muscle fibers in the paretic muscles. There are mixed results for effects on muscle fiber CSA, but there is some evidence of specific atrophy of type II muscle fibers. Impact: Changes in paretic skeletal muscle fibers of individuals with stroke may explain, in part, the substantial losses in strength and power in this population. Interventions to restore type II muscle fiber size may benefit people with stroke.

Personal Activity Intelligence (PAI) e-Health Program in People with Type 2 Diabetes: A Pilot Randomized Controlled Trial

Article

Jul 2021

Introduction: Innovative strategies are needed to enable people with type 2 diabetes (T2D) to self-manage physical activity (PA). Personal Activity Intelligence (PAI) is a new metric that uses the heart rate response to PA to inform the user as to whether they are doing enough PA to reduce the risk of premature mortality. The PAI score reflects PA over the previous seven days with the goal to maintain a score ≥ 100. To investigate the feasibility, acceptability and efficacy of the PAI e-Health Program in people with T2D. Methods: 30 participants with T2D who were not meeting PA guidelines were randomly assigned to 12 weeks of either 1) PAI e-Health Program or 2) PA attention control. The PAI e-Health Program consisted of receiving a wrist-worn heart rate monitor and an app with the PAI metric, and attending 4x2hr weekly sessions of exercise and counseling. Feasibility and acceptability of the Program were evaluated by achievement of a PAI score ≥ 100 and participant feedback. Efficacy was determined from changes in glycemic control, cardiorespiratory fitness, exercise capacity (time-on-test), body composition, sleep time and health-related quality of life. Results: Program participants in the PAI e-Health Program had a mean ± SD PAI score of 119.7 ± 60.6 and achieved ≥100 PAI on 56.4% of the days. The majority of participants (80%) intended to continue to use PAI monitoring. Compared to control, the PAI group significantly improved their exercise capacity (mean difference, 95% confidence interval) (63 s, 17.9 to 108.0 s), sleep time (67.2 min, 7.2 to 127.1), total percent body fat (-1.3%, -2.6 to -0.1%) and gynoid fat percent (-1.5%, -2.6 to -0.5). Conclusions: The PAI e-Health Program is feasible, acceptable and efficacious in people with T2D.

Full Familiarisation Is Not Required for the Self-Paced 1 km Treadmill Walk to Predict Peak Oxygen Uptake in Phase IV Cardiac Patients

Article

Full-text available

Feb 2024

Exercise is a recommended part of phase IV cardiovascular rehabilitation (CR). The 1 km treadmill walk test (1-KTWT) is a submaximal continuous exercise test to predict cardiorespiratory fitness in patients with cardiovascular disease. We examined physiological, metabolic and subjective responses in patients with cardiovascular disease with self-selected, unchanging walking speed for two 1-KTWTs. Fifteen men (age: 65 ± 9 yr, height: 174 ± 5 cm, body mass: 86 ± 17 kg, BMI: 28.5 ± 5.5 kg·m−2, body fat%: 27.7 ± 7.5%, 10 on beta-blockers) were recruited from phase IV CR groups in the United Kingdom. Participants established a self-selected walking speed for the 1-KTWT and performed the 1-KTWT on separate days with recording of physiological responses to predict V˙O2peak with equations. For the two 1-KTWTs, no differences existed for walking speed, mean and maximal heart rates, oxygen uptake, predicted V˙O2peak (1st 1-KTWT (range: 41–78% V˙O2peak, 95%CI, 53–65; 2nd 1-KTWT range: 43–78% V˙O2peak, 95%CI, 52–65) and rating of perceived exertion. In phase IV cardiac patients, the 1-KTWT with self-selected, unchanging walking speed can be used for V˙O2peak prediction without the need for a full familiarisation. The self-selected constant walking speed for the first 1-KTWT can be used to support nonsupervised physical activity for phase IV CR patients.

Low skeletal muscle mass is associated with low aerobic capacity and increased mortality risk in patients with coronary heart disease – a CARE CR study

Article

Full-text available

Aug 2018

Background In patients with chronic heart failure, there is a positive linear relationship between skeletal muscle mass (SMM) and peak oxygen consumption (VO2peak); an independent predictor of all‐cause mortality. We investigated the association between SMM and VO2peak in patients with coronary heart disease (CHD) without a diagnosis of heart failure. Methods Male patients with CHD underwent maximal cardiopulmonary exercise testing and dual X‐ray absorptiometry assessment. VO2peak, the ventilatory anaerobic threshold and peak oxygen pulse were calculated. SMM was expressed as appendicular lean mass (lean mass in both arms and legs) and reported as skeletal muscle index (SMI; kg m⁻²), and as a proportion of total body mass (appendicular skeletal mass [ASM%]). Low SMM was defined as a SMI <7·26 kg m⁻², or ASM% <25·72%. Five‐year all‐cause mortality risk was calculated using the Calibre 5‐year all‐cause mortality risk score. Results Sixty patients were assessed. Thirteen (21·7%) had low SMM. SMI and ASM% correlated positively with VO2peak (r = 0·431 and 0·473, respectively; P<0·001 for both). SMI and ASM% predicted 16·3% and 12·9% of the variance in O2peak, respectively. SMI correlated most closely with peak oxygen pulse (r = 0·58; P<0·001). SMI predicted 40·3% of peak O2/HR variance. ASM% was inversely associated with 5‐year all‐cause mortality risk (r = −0·365; P = 0·006). Conclusion Skeletal muscle mass was positively correlated with VO2peak in patients with CHD. Peak oxygen pulse had the strongest association with SMM. Low ASM% was associated with a higher risk of all‐cause mortality. The effects of exercise and nutritional strategies aimed at improving SMM and function in CHD patients should be investigated.

Skeletal muscle fiber-type-specific changes in markers of capillary and mitochondrial content after low-volume interval training in overweight women

Article

Full-text available

Mar 2018

High-intensity interval training (HIIT) enhances skeletal muscle oxygen delivery and utilization but data are limited regarding fiber-specific adaptations in humans. We examined the effect of 18 sessions of HIIT (10 × 60-sec cycling intervals at ~90% HRmax, interspersed by 60-sec of recovery) over 6 weeks on markers of microvascular density and oxidative capacity in type I and II fibers in healthy but sedentary young women (Age: 26 ± 7 years; BMI: 30 ± 4 kg·m-2; VO2peak: 2.16 ± 0.45 L·m-1). Immunohistochemical analyses of muscle cross sections revealed a training-induced increase in capillary contacts per fiber in type I fibers (PRE: 4.38 ± 0.37 vs. POST: 5.17 ± 0.80; main effect, P < 0.05) and type II fibers (PRE: 4.24 ± 0.55 vs. POST: 4.92 ± 0.54; main effect, P < 0.05). The capillary-to-fiber ratio also increased after training in type I fibers (PRE: 1.53 ± 1.44 vs. POST: 1.88 ± 0.38; main effect, P < 0.05) and type II fibers (PRE: 1.45 ± 0.19 vs. POST: 1.76 ± 0.27; main effect, P < 0.05). Muscle oxidative capacity as reflected by the protein content of cytochrome oxidase IV also increased after training in type I fibers (PRE: 3500 ± 858 vs. POST: 4442 ± 1377 arbitrary units; main effect, P < 0.01) and type II fibers (PRE: 2632 ± 629 vs. POST: 3863 ± 1307 arbitrary units; main effect, P < 0.01). We conclude that short-term HIIT in previously inactive women similarly increases markers of capillary density and mitochondrial content in type I and type II fibers.

Muscle fibre capillarization is a critical factor in muscle fibre hypertrophy during resistance exercise training in older men

Article

Full-text available

Aug 2016

Background: Adequate muscle fibre perfusion is critical for the maintenance of muscle mass; it is essential in the rapid delivery of oxygen, nutrients and growth factors to the muscle, stimulating muscle fibre growth. Muscle fibre capillarization is known to decrease substantially with advancing age. However, whether (relative) low muscle fibre capillarization negatively impacts the muscle hypertrophic response following resistance exercise training in older adults is unknown. Methods: Twenty-two healthy older men (71 ± 1 years) performed 24 weeks of progressive resistance type exercise training. To assess the change in muscle fibre characteristics, percutaneous biopsies from the vastus lateralis muscle were taken before and following 12 and 24 weeks of the intervention programme. A comparison was made between participants who had a relatively low type II muscle fibre capillary-to-fibre perimeter exchange index (CFPE; LOW group) and high type II muscle fibre CFPE (HIGH group) at baseline. Type I and type II muscle fibre size, satellite cell, capillary content and distance between satellite cells to the nearest capillary were determined by immunohistochemistry. Results: Overall, type II muscle fibre size (from 5150 ± 234 to 6719 ± 446 µm(2) , P < 0.05) and satellite cell content (from 0.058 ± 0.006 to 0.090 ± 0.010 satellite cells per muscle fibre, P < 0.05) had increased significantly in response to 24 weeks of resistance exercise training. However, these improvements where mainly driven by differences in baseline type II muscle fibre capillarization, whereas muscle fibre size (from 5170 ± 390 to 7133 ± 314 µm(2) , P < 0.05) and satellite cell content (from 0.059 ± 0.009 to 0.102 ± 0.017 satellite cells per muscle fibre, P < 0.05) increased significantly in the HIGH group, no significant changes were observed in LOW group following exercise training. No significant changes in type I and type II muscle fibre capillarization were observed in response to 12 and 24 weeks of resistance exercise training in both the LOW and HIGH group. Conclusions: Type II muscle fibre capillarization at baseline may be a critical factor for allowing muscle fibre hypertrophy to occur during prolonged resistance exercise training in older men.

Maximal oxygen uptake is proportional to muscle fiber oxidative capacity - from chronic heart failure patients to professional cyclists

Article

Full-text available

Sep 2016

VO2max during whole-body exercise is presumably constrained by oxygen delivery to mitochondria rather than by mitochondria's ability to consume oxygen. Humans and animals have been reported to exploit only 60-80% of their mitochondrial oxidative capacity at VO2max However, ex vivo quantification of mitochondrial overcapacity is complicated by isolation or permeabilization procedures. An alternative method for estimating mitochondrial oxidative capacity is via enzyme histochemical quantification of succinate dehydrogenase (SDH) activity. We determined to what extent V̇O2max attained during cycling exercise differs from mitochondrial oxidative capacity predicted from SDH activity of m. vastus lateralis in chronic heart failure patients, healthy controls and cyclists. VO2max was assessed in 20 healthy subjects and 28 cyclists and SDH activity was determined from biopsy cryosections of m. vastus lateralis using quantitative histochemistry. Similar data from our laboratory of 14 chronic heart failure patients and 6 controls were included. Mitochondrial oxidative capacity was predicted from SDH activity using estimated skeletal muscle mass and the relationship between ex vivo fiber VO2max and SDH activity of isolated single muscle fibers and myocardial trabecula under hyperoxic conditions. Mitochondrial oxidative capacity predicted from SDH activity was related (r2=0.89, p<0.001) to VO2max measured during cycling in subjects with VO2max ranging from 9.8 to 79.0 ml kg-1 min-1 VO2max measured during cycling was on average 90±14% of mitochondrial oxidative capacity. We conclude that human VO2max is related to mitochondrial oxidative capacity predicted from skeletal muscle SDH activity. Mitochondrial oxidative capacity is likely marginally limited by oxygen supply to mitochondria.

Satellite cells in human skeletal muscle plasticity

Article

Full-text available

Oct 2015

Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodeling. Our knowledge of the role of satellite cells in muscle fiber adaptation has traditionally relied on in vitro cell and in vivo animal models. Over the past decade, a genuine effort has been made to translate these results to humans under physiological conditions. Findings from in vivo human studies suggest that satellite cells play a key role in skeletal muscle fiber repair/remodeling in response to exercise. Mounting evidence indicates that aging has a profound impact on the regulation of satellite cells in human skeletal muscle. Yet, the precise role of satellite cells in the development of muscle fiber atrophy with age remains unresolved. This review seeks to integrate recent results from in vivo human studies on satellite cell function in muscle fiber repair/remodeling in the wider context of satellite cell biology whose literature is largely based on animal and cell models.

Mitochondrial adaptations to high intensity interval training in older females and males

Article

May 2019

Introduction: High intensity interval training (HIIT) has shown to be as effective as moderate intensity endurance training to improve metabolic health. However, the current knowledge on the effect of HIIT in older individuals is limited and it is uncertain whether the adaptations are sex specific. The aim was to investigate effects of HIIT on mitochondrial respiratory capacity and mitochondrial content in older females and males. Methods: Twenty-two older sedentary males (n = 11) and females (n = 11) completed 6 weeks of supervised HIIT 3 days per week. The training consisted of 5 × 1 min cycling (124 ± 3% of max power output at session 2–6 and 135 ± 3% of max power output at session 7–20) interspersed by 1½ min recovery. Before the intervention and 72 h after last training session a muscle biopsy was obtained and mitochondrial respiratory capacity, citrate synthase activity and proteins involved in mitochondria metabolism were assessed. Furthermore, body composition and ⩒O2max were measured. Results: ⩒O2max increased and body fat percentage decreased after HIIT in both sexes (p < 0.05). In addition, CS activity and protein content of MnSOD and complex I-V increased in both sexes. Coupled and uncoupled mitochondrial respiratory capacity increased only in males. Mitochondrial respiratory capacity normalised to CS activity (intrinsic mitochondrial respiratory capacity) did not change following HIIT. Conclusion: HIIT induces favourable adaptions in skeletal muscle in older subjects by increasing mitochondrial content, which may help to maintain muscle oxidative capacity and slow down the process of sarcopenia associated with ageing.

Skeletal muscle fiber characteristics in patients with chronic heart failure: Impact of disease severity and relation with muscle oxygenation during exercise

Article

Aug 2018

The influence of capillarization on satellite cell pool expansion and activation following exercise-induced muscle damage in healthy young men

Article

Jan 2018

Key points: Skeletal muscle stem cells (satellite cells) play a crucial role in repair and remodelling of muscle in response to exercise. Satellite cells are in close spatial proximity to muscle capillaries and therefore may be influenced by them. In this study, we describe the activation and expansion of the satellite cell pool in response to eccentric contraction-induced muscle damage in individuals with significantly different levels of muscle capillarization. Individuals with greater capillarization and capacity for muscle perfusion demonstrated enhanced activation and/or expansion of the satellite cell pool allowing for an accelerated recovery of muscle function. These results provide insight into the critical relationship between muscle capillarization and satellite cells during skeletal muscle repair. Abstract: Factors that determine the skeletal muscle satellite cell (SC) response remain incompletely understood. It is known, however, that SC activation status is closely related to the anatomical relationship between SCs and muscle capillaries. We investigated the impact of muscle fibre capillarization on the expansion and activation status of SCs following a muscle-damaging exercise protocol in healthy young men. Twenty-nine young men (21 ± 0.5 years) performed 300 unilateral eccentric contractions (180 deg s-1) of the knee extensors. Percutaneous muscle biopsies from the vastus lateralis and blood samples from the antecubital vein were taken prior to (Pre) exercise and at 6, 24, 72 and 96 h of post-exercise recovery. A comparison was made between subjects who had a relative low mixed muscle capillary-to-fibre perimeter exchange index (CFPE; Low group) and high mixed muscle CFPE index (High group) at baseline. Type I and type II muscle fibre size, myonuclear content, capillarization, and SC response were determined via immunohistochemistry. Overall, there was a significant correlation (r = 0.39; P < 0.05) between the expansion of SC content (change in total Pax7+cells/100 myofibres) 24 h following eccentric exercise and mixed muscle CFPE index. There was a greater increase in activated SCs (MyoD+/Pax7+cells) in the High as compared to the Low CFPE group 72 h following eccentric exercise (P < 0.05). The current study provides further evidence that muscle fibre capillarization may play an important role in the activation and expansion of the SC pool during the process of skeletal muscle repair.

Superior mitochondrial adaptations in human skeletal muscle after interval compared to continuous single-leg cycling matched for total work

Article

Jul 2016
J PHYSIOL-LONDON

Key points: A classic unresolved issue in human integrative physiology involves the role of exercise intensity, duration and volume in regulating skeletal muscle adaptations to training. We employed counterweighted single-leg cycling as a unique within-subject model to investigate the role of exercise intensity in promoting training-induced increases in skeletal muscle mitochondrial content. Six sessions of high-intensity interval training performed over 2 weeks elicited greater increases in citrate synthase maximal activity and mitochondrial respiration compared to moderate-intensity continuous training matched for total work and session duration. These data suggest that exercise intensity, and/or the pattern of contraction, is an important determinant of exercise-induced skeletal muscle remodelling in humans. Abstract: We employed counterweighted single-leg cycling as a unique model to investigate the role of exercise intensity in human skeletal muscle remodelling. Ten young active men performed unilateral graded-exercise tests to measure single-leg V̇O2, peak and peak power (Wpeak ). Each leg was randomly assigned to complete six sessions of high-intensity interval training (HIIT) [4 × (5 min at 65% Wpeak and 2.5 min at 20% Wpeak )] or moderate-intensity continuous training (MICT) (30 min at 50% Wpeak ), which were performed 10 min apart on each day, in an alternating order. The work performed per session was matched for MICT (143 ± 8.4 kJ) and HIIT (144 ± 8.5 kJ, P > 0.05). Post-training, citrate synthase (CS) maximal activity (10.2 ± 0.8 vs. 8.4 ± 0.9 mmol kg protein-1 min-1 ) and mass-specific [pmol O2 •(s•mg wet weight)-1 ] oxidative phosphorylation capacities (complex I: 23.4 ± 3.2 vs. 17.1 ± 2.8; complexes I and II: 58.2 ± 7.5 vs. 42.2 ± 5.3) were greater in HIIT relative to MICT (interaction effects, P < 0.05); however, mitochondrial function [i.e. pmol O2 •(s•CS maximal activity)-1 ] measured under various conditions was unaffected by training (P > 0.05). In whole muscle, the protein content of COXIV (24%), NDUFA9 (11%) and mitofusin 2 (MFN2) (16%) increased similarly across groups (training effects, P < 0.05). Cytochrome c oxidase subunit IV (COXIV) and NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) were more abundant in type I than type II fibres (P < 0.05) but training did not increase the content of COXIV, NDUFA9 or MFN2 in either fibre type (P > 0.05). Single-leg V̇O2, peak was also unaffected by training (P > 0.05). In summary, single-leg cycling performed in an interval compared to a continuous manner elicited superior mitochondrial adaptations in human skeletal muscle despite equal total work.

The Global Burden of Cardiovascular Disease: EDITORIAL

Article

May 2016

Douglas Moodie

Both Traditional and Stair Climbing–based HIIT Cardiac Rehabilitation Induce Beneficial Muscle Adaptations

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