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. Author manuscript; available in PMC: 2025 Feb 1.
Published in final edited form as: Med Sci Sports Exerc. 2023 Sep 12;56(2):266–276. doi: 10.1249/MSS.0000000000003291

Time-Efficient, High-Resistance Inspiratory Muscle Strength Training Increases Exercise Tolerance in Midlife and Older Adults

Daniel H Craighead 1, Kaitlin A Freeberg 1, Thomas C Heinbockel 1, Matthew J Rossman 1, Rachel A Jackman 1, Narissa P McCarty 1, Lindsey R Jankowski 1, Travis Nemkov 2, Julie A Reisz 2, Angelo D’Alessandro 2, Michel Chonchol 3, E Fiona Bailey 4, Douglas R Seals 1
PMCID: PMC10840713  NIHMSID: NIHMS1928269  PMID: 37707508

Abstract

Purpose:

To determine if time-efficient, high-resistance inspiratory muscle strength training (IMST), comprising 30 inhalation-resisted breaths per day, improves cardiorespiratory fitness, exercise tolerance, physical function and/or regional body composition in healthy midlife and older adults.

Methods:

We performed a double-blind, randomized, sham-controlled clinical trial (NCT03266510) testing 6 weeks of IMST (30 breaths/day, 6 days/week, 55%−75% maximal inspiratory pressure) versus low-resistance sham training (15% maximal inspiratory pressure) in healthy men and women aged 50–79 years. Subjects performed a graded treadmill exercise test to exhaustion, physical performance battery (e.g., handgrip strength, leg press), and body composition testing (dual x-ray absorptiometry) at baseline and after 6 weeks of training.

Results:

Thirty-five participants (17 women, 18 men) completed high-resistance IMST (n=17) or sham training (n=18). Cardiorespiratory fitness (V̇O2peak) was unchanged, but exercise tolerance, measured as treadmill exercise time during a graded exercise treadmill test, increased with IMST (baseline: 539±42s, end-intervention: 606±42s; p=0.01) but not sham training (baseline: 562±39s, end-intervention: 553±38s; p=0.69). IMST increased peak respiratory exchange ratio (baseline: 1.09±0.02, end-intervention: 1.13±0.02; p=0.012), peak ventilatory efficiency (baseline: 25.2±0.8, end-intervention: 24.6±0.8; p=0.036) and improved submaximal exercise economy (baseline: 23.5±1.1ml/kg/min, end-intervention: 22.1±1.1ml/kg/min; p<0.001); none of these factors were altered by sham training (all p>0.05). Changes in plasma acylcarnitines (targeted metabolomics analysis) were consistently positively correlated with changes in exercise tolerance following IMST but not sham training. IMST was associated with regional increases in thorax lean mass (+4.4%; p=0.06) and reductions in trunk fat mass (−4.8%; p=0.04); however, peripheral muscle strength, muscle power, dexterity and mobility were unchanged.

Conclusions:

These data suggest that high-resistance IMST is an effective, time-efficient lifestyle intervention for improving exercise tolerance in healthy midlife and older adults.

Keywords: ACYLCARNITINES, CARDIORESPIRATORY FITNESS, BODY COMPOSITION, PHYSICAL FUNCTION

INTRODUCTION

Advancing age is associated with declines in both cardiorespiratory fitness (defined as the maximal capacity to utilize oxygen for physical activity) (1) and exercise tolerance (defined as the ability to maintain physical activity) (2). Reductions in cardiorespiratory fitness and exercise tolerance are associated with increased risk of all-cause mortality (3), as well as cardiovascular disease (CVD)-related mortality (4, 5), the leading cause of death in developed and developing countries (6). The number of older adults is expected to rapidly increase in the coming decades. As such, establishing interventions that can improve cardiorespiratory fitness and exercise tolerance in midlife and older adults (i.e., adults aged ≥50 years) is an important biomedical and public health priority.

Guideline-based aerobic exercise (i.e., ≥150 minutes of moderate-intensity or ≥75 minutes of vigorous-intensity aerobic exercise per week) can improve cardiorespiratory fitness and exercise tolerance (7, 8). However, <40% of midlife and older adults in the United States meet aerobic exercise guidelines, in large part due to perceived lack of time (9). Accordingly, there is a need for time-efficient forms of physical training that also can improve cardiorespiratory fitness and exercise tolerance (9).

High-resistance inspiratory muscle strength training (IMST) is a low-volume, time-efficient form of intensive respiratory exercise that improves respiratory muscle strength. Although specific patterns of respiratory muscle activation during IMST have not been fully characterized, it is expected that IMST activates the diaphragm and may engage other muscle groups, such as those of the head and neck (e.g., scalenes), upper airway (e.g., cricothyroid), thorax (e.g., external intercostals), or back (e.g., erector spinae) (10, 11). High-resistance IMST protocols comprise only 30 resisted inspirations and can be completed in as little as ~5 minutes per day, overcoming time-availability related barriers associated with conventional aerobic exercise (12). Our laboratory recently completed a double-blind, randomized, sham-controlled clinical trial testing high-resistance IMST in midlife and older adults with above-normal initial systolic blood pressure (i.e., ≥120 mmHg). This trial demonstrated that 6 weeks of high-resistance IMST, consisting of 30 breaths per day at 75% maximal inspiratory pressure (PIMAX), 6 days per week is safe, promotes excellent rates of adherence (94% of prescribed training sessions completed), lowers casual (resting) blood pressure and improves vascular endothelial function (13). Although our initial report demonstrated efficacy of time-efficient, high-resistance IMST for improving cardiovascular function (13), whether this intervention can increase cardiorespiratory fitness or exercise tolerance in midlife and older adults has not been established.

Inspiratory training protocols are reported to increase cardiorespiratory fitness and exercise tolerance, particularly in patient populations (14, 15), and to improve sports performance in endurance athletes (16). Likely mechanisms mediating these improvements in performance are greater respiratory muscle endurance and reduced cardiovascular strain from respiratory work (17), as well as reduced perceptions of breathlessness (18). In addition, myokines released from the respiratory muscles during inspiratory exercise may serve as signaling molecules for improving function (19, 20). However, the efficacy of IMST for improving physical-performance outcomes in healthy midlife and older adults is unclear. A previous trial in healthy older adults found that more frequent IMST at a lower intensity (30 breaths at 50% PIMAX, 2x/day) did not improve functional capacity after 8 weeks (21). However, 6 weeks of high-resistance IMST (30 breaths at 75% PIMAX) was sufficient to improve respiratory exercise performance (17); although it is unknown if this higher intensity, shorter duration IMST program may evoke improvements in whole-body physical performance. On the other hand, IMST was reported to improve select measures of mobility, balance, and trunk strength in older adults (22).

Identifying molecular transducers that underlie the health effects of physical activity is an important research goal as this information can help identify strategies and therapeutic targets to improve and preserve health (23). Acylcarnitines are involved in fatty acid metabolism and mitochondrial function (24), important processes that impact cardiorespiratory fitness and exercise tolerance. Higher plasma acylcarnitine levels are associated with a younger biological age (25), are observed in healthy adults following aerobic exercise training, and are associated with improvements in exercise capacity (26, 27). However, it is unknown if circulating acylcarnitines may be a molecular transducer of IMST-induced changes in cardiorespiratory fitness or exercise tolerance.

Finally, changes in regional body composition with physical activity are related to improvements in physical performance in older adults (28). Thus, there is a need to more thoroughly interrogate changes in regional body composition with IMST.

To address these research gaps, we analyzed outcomes from our 6-week trial of high-resistance IMST in midlife and older adults to determine if high-resistance IMST can increase cardiorespiratory fitness and/or exercise tolerance, defined as peak oxygen consumption (V̇O2peak) and total treadmill exercise time, respectively, during an incremental exercise test to exhaustion. To examine how high-resistance IMST may impact these outcomes, we evaluated cardiorespiratory variables during peak exercise and at a fixed submaximal workload. In addition, we evaluated whether any improvements in exercise capacity observed were related to baseline concentrations or changes in the levels of plasma acylcarnitines. Regional lean mass, fat mass, and bone mineral density, along with measures of physical function including muscle strength, power, mobility, and dexterity also were measured.

We hypothesized that 6 weeks of high-resistance IMST, but not sham training, would improve cardiorespiratory fitness and exercise tolerance, and that these improvements would be related to plasma acylcarnitine levels. We also hypothesized that IMST, but not sham training, would improve lean mass and fat mass in regions targeted by IMST, and improve other measures of strength, power, mobility, and dexterity.

METHODS

All procedures were reviewed and approved by the Institutional Review Board at the University of Colorado Boulder (approval # 17–0151). The nature, benefits, and risks of all study procedures were explained to volunteers, and their written informed consent was obtained before participation in the study. The study was registered on clinicaltrials.gov (NCT03266510).

Participants, Study Design, and Intervention

This study reports outcomes from a double-blind, randomized, sham-controlled, parallel group design clinical trial testing 6 weeks of high-resistance IMST versus low-resistance sham (control) training. Otherwise healthy men and postmenopausal women aged 50 to 79 years who were free of chronic overt disease, with a casual systolic blood pressure ≥120 mmHg were included in this study. Potential participants were excluded if they had fasting plasma glucose ≥126 mg/dL, had total cholesterol ≥240 mg/dL, had severe obesity (body mass index >40 kg/m2), were not weight stable (>3 kg change in body mass during the past 3 months), had uncontrolled thyroid disease, or had alcohol dependence. Participants were habitually active, participating in sufficient leisure time physical activity to meet physical activity guidelines but not performing structured exercise training. As reported previously (13), subjects were randomized to perform high-resistance IMST or low-resistance sham training. Both groups trained using the POWERBreathe K3 pressure-threshold inspiratory muscle training device with tapered resistance, whereby inspiratory resistance is altered throughout the duty cycle by a computer-controlled rotary valve. All subjects performed 30 inspiratory maneuvers (5 sets of 6 breaths, 1 minute rest between sets), 6 days per week, for 6 weeks. Subjects randomized to high-resistance IMST trained at 55% PIMAX during week 1, 65% PIMAX during week 2, and 75% PIMAX during weeks 3–6. The Sham group trained at 15% PIMAX throughout the entire intervention. One training session per week was observed by an unblinded research assistant. The remaining 5 training sessions each week were performed unsupervised at home with adherence monitored via the internal data storage of the POWERBreathe K3 device. Average inspiratory power and volume for each training session also were monitored by the POWERBreathe K3. During their first supervised training session, participants received instructions on how to properly perform IMST or sham training from a trained research assistant; proper technique was reinforced during all supervised training sessions.

PIMAX was assessed at baseline and during weekly supervised training sessions throughout the intervention using standardized procedures outlined by the American Thoracic Society and European Respiratory Society (29). Participants performed a series of maximal inspiratory efforts against a near-infinite resistance using a custom pressure transducer (Omegadyne, Inc.). Inspiratory efforts were performed until the 3 largest pressures generated were within 5% of each other; PIMAX was defined as the average of these 3 efforts. Absolute training intensity was adjusted weekly to maintain the training stimulus.

Measurements

All measurements were performed at the University of Colorado Boulder, Clinical Translational Research Center or Integrative Physiology of Aging Laboratory. All outcome measures were assessed before and at the end of 6 weeks of high-resistance IMST or sham training. Cardiorespiratory, physical function, and body composition measurements were obtained ~2 hours after a snack or light meal and at least 24 hours after abstaining from alcohol and strenuous exercise. All blood samples were obtained from an antecubital vein after a 12-hour fast and at least 24 hours after consuming alcohol, exercising, and taking over-the-counter medications or dietary supplements. All end-intervention measurements were made between 24 and 48 hours after the most recent IMST or sham training session to eliminate potential interference from acute effects of the intervention but prevent detraining. Habitual physical activity levels were assessed before and at the end of the 6-week intervention period via wrist-worn tri-axial accelerometry (GeneActiv, 3-day recording).

Cardiorespiratory Fitness.

Peak aerobic capacity (V̇O2peak) was determined at baseline and end-intervention via open circuit respirometry during an incremental treadmill exercise test to volitional exhaustion (modified Balke protocol). Starting treadmill was speed tailored to reach ~75% of each participant’s age-predicted maximal heart rate. Treadmill grade was initially set to 0% and then was increased by 2% every 2 minutes until volitional exhaustion, which was determined as the participant-expressed inability to continue treadmill exercise, despite strong encouragement to continue by the study team. For each subject, treadmill speed and the change in grade was controlled such that workloads for each stage of the incremental test would be matched between baseline and end-intervention timepoints. Breath-by-breath expired gas volume and composition were collected and analyzed using the Ultima CPX metabolic stress testing system. Breath-by-breath data were converted into 30-second averages; peak exercise data are the from the final 30 seconds of exercise while submaximal exercise data are from the final 30 seconds of a completed stage. All measurements were normalized to standard temperature and pressure dry values by measuring temperature, humidity, and pressure.

Exercise tolerance, an independent risk factor for all-cause mortality (3) and CVD (4), was assessed as total treadmill exercise time during the incremental treadmill exercise test. We have used this protocol extensively to assess changes in cardiorespiratory fitness and exercise tolerance across interventions (30, 31).

Minute ventilation (V̇E), volume of expired carbon dioxide (V̇CO2), respiratory exchange ratio (RER), respiratory rate, and tidal volume also were assessed during peak exercise via open circuit respirometry. Ventilatory efficiency at peak exercise was determined as V̇E/V̇CO2 (32). In addition to the measures of respiratory function, heart rate was measured via 12-lead ECG and rating of perceived exercise (RPE) was assessed with the Borg 6–20 scale during peak exercise.

The same measures of respiratory function, heart rate, and RPE also were assessed at the starting treadmill workload for each subject and the workload that most closely elicited 80% of V̇O2peak at the baseline timepoint to assess changes in cardiorespiratory function during submaximal exercise. Exercise economy was calculated as the rate of oxygen consumption during the last 30 seconds of these submaximal workloads. Within each subject, submaximal cardiorespiratory function was assessed at the same absolute workload (i.e., same treadmill speed and grade) at baseline and end-intervention.

Plasma Metabolomics.

Plasma samples for metabolomics were prepared as described previously (13). A specific analysis of plasma acylcarnitines was performed using high-throughput mass spectrometry on a Vanquish UHPLC – Q Exactive MS as previously described (13).

Physical Function.

As described previously (33), the NIH Toolbox Motor Battery grip strength test and 9-hole pegboard test were used to assess upper body strength and dexterity, respectively. Grip strength was determined as the maximum force produced on a dynamometer over 3 attempts with the dominant hand. Results from the pegboard test are presented as the average from 2 attempts with the dominant hand.

In addition, mobility (stair ascent test), lower body strength and power (bilateral leg press test) also were evaluated as described previously (34, 35). The stair ascent test was determined as the average of 3 trials. Lower body strength was defined as the highest force produced from a maximum of 8 trials, while lower body power was determined as the maximal power produced during 5 leg press attempts with resistance set to 70% of an individual’s maximal lower body leg strength.

Body Composition.

Total body and segmental fat mass, lean mass, and bone mineral density were measured via dual energy X-ray absorptiometry (DXA; Lunar Prodigy 8915, GE Medical Systems). Segmental lean and fat masses were measured from the DXA scans for the trunk, arms, legs, head/neck, and thorax by the enCORE 2007 software platform. Segmental bone mineral density was determined for the above locations and for the ribs, pelvis and spine.

Data Analysis

Statistical analyses were performed with SPSS version 27. Continuous variables were assessed using a repeated measures analysis with a mixed effects model in which the outcome of interest (e.g., total treadmill exercise time) was the dependent variable and the timepoint (baseline, end-intervention), group (IMST, sham) and the group by time interaction were independent variables. Sidak’s post-hoc test was used to control for multiple comparisons. The Chi-squared test was used to assess between-group differences in categorical variables. Simple linear regression was used to compare baseline levels or the change in acylcarnitine levels with the change in exercise tolerance; separate regressions were performed for the entire subject cohort and each subject group. When available, data expressed as a percent of normative predicted values are presented in the Supplemental Digital Content (see Supplemental Tables 1 – 6, Supplemental Digital Content). Unless otherwise noted, data are expressed as mean±SEM. Statistical significance was set a priori as α=0.05. A separate power analysis for the outcomes reported herein was not performed as these are exploratory outcomes from a trial powered to detect changes in casual systolic blood pressure (13).

RESULTS

Participants

As reported previously, a total of 64 subjects signed the informed consent to participate in this study. Twenty-six of these subjects were excluded because they did not meet study inclusion criteria or withdrew voluntarily, resulting in 38 subjects being equally randomized to the IMST or sham training groups. Two subjects subsequently were withdrawn during the intervention, resulting in a final sample size of 36 participants. A total of 35 subjects were included in the final analysis (IMST n=17, sham n=18). One participant from the trial did not complete measurements associated with this analysis because of scheduling availability. Participant characteristics between groups were well matched (Table 1). There were no differences between groups in age, sex distribution, resting heart rate, blood lipids, fasting glucose, height, and weight at baseline (all p>0.05). Additionally, none of these characteristics changed across the 6-week intervention (all p>0.05). Importantly, levels of moderate-to-vigorous physical activity did not change across the intervention in either group (all p>0.05), indicating that changes in physical activity outside of the prescribed inspiratory training protocol did not influence our results. Consistent with the findings in our entire cohort, systolic blood pressure (p<0.001) and diastolic blood pressure (p=0.050) decreased, and PIMAX (both as absolute value and percent predicted value (36)) increased (p=0.001) with IMST but were unchanged with sham training. Average inspiratory power during training was higher in the IMST group compared to sham (IMST: 7.2±0.9 watts, sham: 4.0±0.6 watts; p=0.004), while average inspiratory volume during training was higher in the sham group compared to IMST (IMST: 1.4±0.1 L, sham: 2.1±0.1 L; p=0.001).

Table 1.

Subject characteristics.

Sham IMST
Pre Post Pre Post
Age (years) 67 ± 2 - 68 ± 2 -
Sex (male/female) 10/8 - 8/9 -
Resting HR (bpm) 63 ± 2 63 ± 3 64 ± 3 62 ± 2
Total Cholesterol (mg/dL) 169 ± 7 172 ± 7 169 ± 5 169 ± 5
HDL Cholesterol (mg/dL) 51 ± 4 51 ± 5 49 ± 4 49 ± 4
LDL Cholesterol (mg/dL) 99 ± 5 101 ± 5 99 ± 4 100 ± 4
Triglycerides (mg/dL) 96 ± 9 99 ± 10 108 ± 12 107 ± 12
Glucose (mg/dL) 91 ± 2 89 ± 1 90 ± 1 90 ± 2
SBP (mmHg) 134 ± 2 131 ± 3 135 ± 2 126 ± 3*
DBP (mmHg) 81 ± 1 81 ± 1 79 ± 2 77 ± 2*
Height (m) 1.71 ± 0.02 -- 1.68 ± 0.02 --
Weight (kg) 80.2 ± 3.8 81.0 ± 3.9 72.9 ± 3.0 72.9 ± 2.9
PIMAX (cmH2O) 94 ± 6 97 ± 5 86 ± 7 100 ± 6*
PIMAX (% predicted) 119 ± 7 124 ± 9 110 ± 8 129 ± 6*
Moderate & Vigorous physical activity (min/week) 232 ± 20 224 ± 26 246 ± 21 261 ± 19
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HR, heart rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure; PIMAX, maximal inspiratory pressure. Data are mean ± SEM.

*

p<0.05 vs. Pre.

Treadmill Exercise

Peak Treadmill Exercise Responses.

Peak exercise responses were not obtained in two subjects, both in the IMST group. One participant elected not to perform the treadmill exercise test, whereas another terminated their end-intervention treadmill test prematurely (i.e., prior to attaining a state of voluntary exhaustion). Therefore, cardiorespiratory fitness data from 33 participants (IMST n=15, sham n=18) are presented. Average treadmill speed during the treadmill exercise test was 3.9±0.2 miles per hour in the IMST group and 3.8±0.2 miles per hour in the sham group, with no difference between groups (p=0.782).

Total treadmill exercise time (Figure 1A), a measure of exercise tolerance and a risk factor for all-cause mortality and cardiovascular diseases (3, 37), increased by 12% in the high-resistance IMST group (baseline: 539±42 s, end-intervention: 606±42 s; p=0.009) but was unchanged in the sham group (baseline: 562±39 s, end-intervention: 553±38 s; p=0.690), such that there was a significant group by time interaction (p=0.026). Cardiorespiratory fitness, expressed as peak oxygen consumption relative to body weight (Figure 1B), did not change with high-resistance IMST (baseline: 27.7±1.6 ml/kg/min, end-intervention: 27.9±1.5 ml/kg/min; p=0.751) or sham training (baseline: 27.0±1.5 ml/kg/min, end-intervention: 26.6±1.4 ml/kg/min; p=0.264) and the interaction effect was not significant (p=0.324).

Figure 1.

Figure 1.

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A) Total treadmill exercise time, a measure of exercise tolerance; B) peak oxygen consumption (V̇O2peak), a measure of cardiorespiratory fitness; and C) respiratory exchange ratio (V̇CO2/V̇O2) at peak exercise before (pre) and at the end of (post) 6 weeks of high-resistance IMST (n=15, 7 men, 8 women) or sham training (n=18, 10 men, 8 women). Statistical analyses were done with a two-way (group x time) ANOVA with Sidak’s post-hoc test. Box indicates interquartile range and mean, whiskers indicate minimum and maximum values; individual data points are shown.

Peak exercise RER (Figure 1C) also increased in the high-resistance IMST group (baseline: 1.09±0.02, end-intervention: 1.13±0.02; p=0.012) but was unchanged in the sham group (baseline: 1.08±0.02, end-intervention: 1.07±0.02; p=0.856), such that there was a significant group by time interaction (p=0.045). As indicated by the increase in RER and unchanged oxygen consumption at peak exercise, the rate of CO2 production at peak exercise increased in the high-resistance IMST group (p=0.044) but did not change in the sham group (p=0.824), with a group by time interaction of p=0.098 (Table 2). There were no changes in V̇E, heart rate, respiratory rate, or RPE at peak exercise in either group (all p>0.050; Table 2). These findings were consistent when results were expressed as a percentage of age- and sex-predicted values (Supplemental Table 1, Supplemental Digital Content, Maximal treadmill exercise: percent predicted values).

Table 2.

Responses to peak treadmill exercise.

Sham IMST
Pre Post Pre Post
V̇O2peak (L/min) 2.17±0.15 2.15±0.14 2.06±0.17 2.04±0.16
V̇CO2peak (L/min) 2.3±0.18 2.3±0.18 2.2±0.20 2.3±0.19*
V̇E (L/min) 56.1±4.5 56.3±4.4 56.6±5.0 57.5±4.9
Respiratory Rate (breaths/min) 38±2 38±2 41±2 40±2
Heart Rate (beats/min) 152±3 152±4 158±4 160±4
RPE (6–20) 16.6±0.4 16.5±0.4 17.3±0.5 17.2±0.5
Tidal volume (L) 1.50 ± 0.12 1.49 ± 0.11 1.39 ± 0.08 1.42 ± 0.09
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V̇O2, volume of oxygen; V̇CO2, volume of carbon dioxide; V̇E, volume expired; RPE, rating of perceived exertion. Data are mean ± SEM.

*

p<0.05 vs. Pre.

Importantly, V̇E/V̇CO2 at peak, a measure of ventilatory efficiency, exercise decreased following high-resistance IMST (baseline: 25.2±0.8, end-intervention: 24.6±0.8; p=0.036) but was unchanged with sham training (baseline: 24.2±0.7, end-intervention: 24.3±0.7; p=0.601); the group by time interaction for peak V̇E/V̇CO2 was p=0.057.

Plasma Acylcarnitines and Exercise Tolerance.

As cardiorespiratory fitness was unchanged, we only examined the association between exercise tolerance and plasma acylcarnitines. There were no significant correlations between baseline plasma acylcarnitine levels and the change in treadmill exercise time when both groups were analyzed together (all p>0.05; Supplemental Table 2, Supplemental Digital Content, Relations between baseline plasma acylcarnitine levels and changes in treadmill exercise time). Baseline levels of propionylcarnitine were inversely related to the change in total treadmill exercise time with high-resistance IMST (R2=0.35, p=0.041; Supplemental Table 2, Supplemental Digital Content). Baseline levels of acetylcarnitine, were positively related to changes in treadmill exercise time in the sham group (R2=0.25, p=0.048; Supplemental Table 2, Supplemental Digital Content). Associations between baseline plasma acylcarnitine levels and the change in treadmill exercise time with either IMST or sham training were not significant (all p>0.05; Supplemental Table 2, Supplemental Digital Content).

Conversely, changes noted in plasma acylcarnitines from baseline to end-intervention were more consistently related to improvements in treadmill exercise time. Of the 19 plasma acylcarnitines measured, changes in 5 plasma acylcarnitines were positively related to increases in treadmill exercise time for the entire cohort (all p<0.05; Supplemental Table 3, Supplemental Digital Content, Relations between changes in plasma acylcarnitine concentrations and changes in treadmill exercise time). For the IMST group, changes in 11 plasma acylcarnitines were positively related to the corresponding changes in treadmill exercise time (all p<0.05; Supplemental Table 3, Supplemental Digital Content). The plasma acylcarnitines with the strongest correlations to treadmill exercise time in the IMST group were those with fatty acyl chains C14:1 (R2=0.57, p=0.003), C10 (R2=0.54, p=0.004), and C12 (R2=0.52, p=0.005), in each case explaining >50% of the variance in the pre- to post-intervention changes in exercise time in response to IMST. In addition, the correlation between the change in treadmill exercise time with IMST and 4 additional acylcarnitines approached statistical significance (p=0.06–0.09; Supplemental Table 3, Supplemental Digital Content), such that 15 of the 19 total markers of acylcarnitine metabolites tended to be moderately to strongly associated with improvements in exercise capacity. Conversely, in the sham group only one plasma acylcarnitine was associated with the changes in treadmill exercise time among individuals (acyl-C8; R2=0.29, p=0.033; Supplemental Table 3, Supplemental Digital Content).

Submaximal Exercise.

Results for submaximal exercise at ~80% V̇O2peak are shown in Figure 2 and Table 3. There was a significant reduction in oxygen consumption (Figure 2) at a submaximal exercise workload after 6 weeks of high-resistance IMST compared to baseline (baseline: 23.5±1.4 ml/kg/min, end-intervention: 22.1±1.3 ml/kg/min; p<0.001); however, submaximal oxygen consumption was unchanged with sham training (baseline: 22.1±1.2 ml/kg/min, end-intervention: 21.7±1.2 ml/kg/min; p=0.288) resulting in a statistically significant group by time interaction (p=0.032). V̇CO2 at the same submaximal workload was reduced in the IMST group (p=0.024), but not in the sham training group (p=0.159) such that there was a significant interaction effect (p=0.010). Similarly, V̇E during submaximal exercise also was reduced following IMST (p=0.034) but not sham training (p=0.591), such that there was a group by time interaction (p=0.053). Submaximal V̇E/V̇CO2 also was unchanged with IMST (p=0.121) and sham (p=0.754) at this submaximal workload. Submaximal heart rate and all other respiratory measures were unchanged following 6 weeks of either IMST or sham training (all p>0.050; Table 3).

Figure 2.

Figure 2.

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Oxygen consumption (V̇O2) at a submaximal workload requiring ~80% of V̇O2peak before (pre) and at the end of (post) 6 weeks of high-resistance IMST (n=15: 7 men, 8 women) or sham training (n=18, 10 men, 8 women). Pre and post workload (i.e., treadmill speed and grade) were kept consistent within subjects. Statistical analyses were done with a two-way (group x time) ANOVA with Sidak’s post-hoc test. Box indicates interquartile range and mean, whiskers indicate minimum and maximum values; individual data points are shown.

Table 3.

Responses to submaximal treadmill exercise at a workload requiring ~80% of maximal oxygen consumption at baseline.

Sham IMST
Pre Post Pre Post
V̇O2 (L/min) 1.77±0.12 1.75±0.12 1.71±0.13 1.62±0.13*
V̇CO2 (L/min) 1.77±0.13 1.73±0.14 1.69±0.14 1.62±0.15*
RER 0.97±0.02 0.96±0.02 0.98±0.02 0.99±0.02
V̇E (L/min) 39.5±2.9 39.0±3.0 41.0±3.1 38.6±3.3*
Respiratory Rate (breaths/min) 29±2 28±2 32±2 31±2
V̇E/V̇CO2 22.9±0.8 23.0±0.7 24.5±0.8 23.7±0.7
Heart Rate (beats/min) 130±4 128±4 135±4 134±4
RPE (6–20) 12.9±0.5 12.4±0.5 13.3±0.6 12.9±0.5
Tidal volume (L) 1.48 ± 0.17 1.42 ± 0.11 1.30 ± 0.09 1.27 ± 0.10
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V̇O2, volume of oxygen; V̇CO2, volume of carbon dioxide; RER, respiratory exchange ratio; V̇E, volume expired; RPE, rating of perceived exertion. Data are mean ± SEM.

*

p<0.05 vs. Pre.

Data from each participant’s lowest workload are presented in Supplemental Table 4 (Supplemental Digital Content, Responses to submaximal treadmill exercise using each participant’s lowest workload). Average %V̇O2peak at this starting workload at baseline was 72±3% in the IMST group and 73±2% in the sham group, though 10 subjects (4 IMST, 6 sham) did reach ~80% V̇O2peak at this initial workload. At this lowest workload, oxygen consumption was reduced with IMST (baseline: 20.0±1.2 ml/kg/min, end-intervention: 19.1±1.1 ml/kg/min; p=0.047) but not sham training (baseline: 19.8±1.3 ml/kg/min, end-intervention: 19.1±1.2 ml/kg/min; p=0.069), with a group by time interaction effect of p=0.788. V̇E also was reduced with IMST (baseline: 34.5±3.6 L/min, end-intervention: 31.2±2.8 L/min; p=0.047) but unchanged with sham training ((baseline: 33.3±2.7 L/min, end-intervention: 33.6±2.9 L/min; p=0.956), with a group by time interaction effect of p=0.062. All other variables at this workload were unchanged with 6 weeks of IMST or sham training (p>0.05).

Physical Function

The time required to complete the stair ascent test was decreased after the intervention (effect of time p=0.025); however, there was no effect of group (p=0.633) or group by time interaction (p=0.835). These results suggest that a learning effect occurred in both groups and that there was not an IMST-induced improvement in mobility. There were no group, time, or interaction effects for all other measures of physical function (all p>0.05) (Table 4). These results were consistent when presented as a percentage of predicted values (Supplemental Table 5, Supplemental Digital Content, Physical function data: percent predicted values).

Table 4.

Physical function measures.

Sham IMST
Pre Post Pre Post
Stair ascent (s) [lower body mobility] 4.29 ± 0.22 4.12 ± 0.24 4.14 ± 0.27 3.94 ± 0.27
9-hole pegboard (s) [dexterity] 22.7 ± 1.0 22.2 ± 0.9 22.1 ± 1.3 21.8 ± 1.1
Grip Strength (kg) [upper body strength] 37.2 ± 2.5 38.3 ± 2.5 35.6 ± 3.0 35.6 ± 2.9
Leg press strength (kg) [lower body strength] 207 ± 20 198 ± 19 172 ± 16 174 ± 16
Leg press power (watts) [lower body power] 1264 ± 129 1290 ± 127 1111 ± 123 1148 ± 122
Open in a new tab

Data are mean ± SEM.

Body Composition

Whole-body lean mass (Supplemental Table 6, Supplemental Digital Content), fat mass (Supplemental Table 7, Supplemental Digital Content), and bone mineral density (Supplemental Table 8, Supplemental Digital Content) were unchanged with intervention in both groups (all p>0.05). There were trends for selective regional changes in lean mass. Lean muscle mass in the thorax increased by 0.56 ± 0.35 kg (4.4%) on average following 6 weeks of IMST (p=0.060), with no change following sham training (+0.07 ± 0.20 kg, p=0.817) and a non-significant interaction effect (p=0.242). In addition, trunk fat mass was reduced by 0.62 ± 0.26 kg (−4.8%) following IMST (p=0.040) but was unchanged with sham training (+0.17 ± 0.32 kg, p=0.566) with an interaction effect of p=0.063. There were no other changes in regional body composition in either group (all p>0.05).

DISCUSSION

In this study, we found that 6 weeks of high-resistance IMST, consisting of 30 breaths per day, 6 days per week, improved exercise tolerance as measured by an increase in total treadmill exercise time, without altering cardiorespiratory fitness, in a group of healthy midlife and older adults. Reduced exercise tolerance is an important risk factor for all-cause mortality and multiple chronic diseases; therefore, these findings suggest that high-resistance IMST is a time-efficient intervention that improves aerobic exercise capacity and may improve health outcomes in midlife and older adults. We also observed multiple IMST-induced adaptations in respiratory function including improved ventilatory efficiency (lower V̇E/V̇CO2) at peak but not submaximal exercise, and improved exercise economy as indicated by a reduced oxygen cost of exercise at submaximal workloads. Moreover, IMST-induced improvements in exercise tolerance appear related to changes in plasma acylcarnitine levels, suggestive of potential changes in substrate availability and/or mitochondrial function as potential underlying mechanisms of action. Finally, high-resistance IMST did not improve other measures of physical function but did modestly impact respiratory exercise-specific segmental body composition.

Treadmill Exercise

Peak Exercise.

Participants randomized to the high-resistance IMST group exhibited a 66 second improvement in treadmill time to exhaustion, whereas treadmill time did not change in those randomized to the sham control group. This indicates that high-resistance IMST can improve exercise tolerance after 6 weeks, even in healthy, habitually active adults. This finding is novel as IMST has previously been shown not improve exercise tolerance in older adults with a high initial functional capacity (18, 21) as the respiratory system is not usually the limiting factor in exercise performance for these individuals. Therefore, it is unlikely that the IMST-induced increase in exercise tolerance that we observed is primarily mediated by changes in the respiratory system. Importantly, in this trial we tested exercise tolerance with an incremental exercise test to exhaustion, the reference-standard measure of exercise capacity. Treadmill time to exhaustion is associated with all-cause and CVD mortality (3, 38); thus, this observation could be associated with reduced risk for CVD and mortality.

The 66 second increase in treadmill exercise time equated to a 12% improvement over baseline. The improvement achieved with an exclusively inspiratory training protocol that requires just ~30 minutes per week compares favorably to those attained with traditional and more arduous aerobic exercise interventions. We have shown previously that ~150–300 minutes per week of conventional aerobic exercise (brisk walking) performed at 70% of maximal heart rate yields an ~15–20% improvement in treadmill exercise tolerance time (30, 31). Thus, high-resistance IMST transduced ~60–80% of the improvement in exercise tolerance observed with aerobic exercise training, with only ~10–20% of the weekly time commitment.

Six weeks of high-resistance IMST had no effect on cardiorespiratory fitness (V̇O2peak). This outcome is similar to our prior investigations of conventional aerobic exercise training in middle-aged and older adults where we detected significant increases in exercise tolerance with no change in V̇O2peak (30, 31). Thus, any improvement in exercise tolerance with IMST is not due to increased peak oxygen consumption. Rather, the reduction in V̇E/V̇CO2 at peak exercise may reflect IMST-related improvements in ventilatory efficiency. Similar improvements have been observed with more time-intensive, IMST protocols in young adult and patient populations (39, 40). An improved ventilatory efficiency would attenuate the respiratory muscle metaboreflex and reduce the volume of blood flow required for the respiratory muscle during high-intensity exercise (41). This blood flow could then be redistributed to the active locomotor muscles, leading to an improvement in exercise tolerance without altering peak oxygen consumption. Importantly, this improvement in ventilatory efficiency was only observed at peak exercise and not during submaximal exercise. Inspiratory muscle fatigue may only occur at high exercise workloads (42), which could explain why this finding was limited to peak exercise. However, as we did not measure diaphragm or leg muscle blood flow, mechanics, or activation, or work of breathing, the potential for a change in ventilatory muscle efficiency with high-resistance IMST at this point is speculative, but merits further investigation.

We also observed an increase in RER at peak exercise. This may indicate that high-resistance IMST facilitates increased anaerobic energy production at peak exercise. IMST has been shown to improve cycling time-trial performance in athletes by increasing anaerobic work capacity (43). This increase in RER also could indicate that high-resistance IMST reduces perceptions of fatigue or effort, allowing individuals to put forth a higher volitional effort during aerobic exercise. However, these potential mechanisms are speculative and additional investigation will be required to determine how high-resistance IMST increases peak RER.

Plasma Acylcarnitines.

Plasma acylcarnitines previously have been associated with aerobic exercise training and changes in exercise capacity (26, 27), making them a potential molecular transducer of exercise tolerance. Accordingly, we considered the possibility that baseline levels or IMST-related changes in acylcarnitine levels might be predictive of improvements in exercise tolerance with IMST. In general, baseline acylcarnitine levels were not associated with improvements in exercise tolerance. Conversely, we observed consistent associations between the change in plasma acylcarnitine levels and changes in exercise tolerance with IMST. Specifically, changes in plasma levels of 11 of the 19 acylcarnitines (~60%) measured were related to changes in treadmill exercise time with high-resistance IMST and another 4 acylcarnitines tended to be related. Importantly, all correlations were positive such that higher levels of acylcarnitines were always associated with greater exercise tolerance. In contrast, only a single acylcarnitine, octanoylcarnitine (C8), was related to changes in exercise tolerance in the sham group. These observations suggest a link between IMST-induced improvements in exercise tolerance and effects on metabolic processes that enhance plasma acylcarnitine abundance, such as fatty acid metabolism and mitochondrial function (24). Thus, these results suggest a pathway for improvements in exercise tolerance with IMST that is unrelated to changes in the respiratory system, which again, is not expected to be a limiting factor for exercise in healthy older adults with normal respiratory muscle function. However, elevated plasma concentrations of acylcarnitines are often observed in obese adults or patients with type 2 diabetes and thought to indicate incomplete fatty acid oxidation stemming from mitochondrial dysfunction (44). Conversely, we have shown that higher plasma acylcarnitines are associated with a younger biological age based on physiological function in healthy adults (25). Given the participants in this study were healthy, physically active adults who demonstrated improvements in exercise tolerance with the high-resistance IMST intervention, it is likely the observed changes in plasma acylcarnitines are indicative of beneficial adaptations.

Submaximal Exercise.

The oxygen cost of exercising at fixed submaximal workloads was modestly reduced by 6% after 6 weeks of high-resistance IMST, indicating that submaximal exercise economy was slightly improved with this intervention. The rate of CO2 production and overall V̇E also were lower during submaximal exercise after IMST versus pre-training. In general, these changes mirror what occurs following aerobic exercise training. This small improvement in exercise economy also could be due to improved respiratory muscle efficiency, as reduced respiratory muscle oxygen consumption would lower whole body V̇O2 measured during exercise; however, this again is speculative as we did not measure respiratory muscle function during whole-body exercise.

Physical Function

Muscle strength and power, dexterity, mobility and balance are important components of physical function that decline with aging and increase the risk for morbidity and mortality (45–47). IMST was reported to improve balance and core muscle function in older adults in a prior investigation (22). In the presented study, 6 weeks of high-resistance IMST did not alter measures of physical function that primarily rely on the arms and legs, such as handgrip or leg press strength. This finding is not surprising given the principle of training specificity. As IMST primarily targets musculature involved in inspiration, improvements in function of the arms and legs may not be anticipated. On the other hand, inspiratory resistive breathing increases adductor pollicis motor unit activation (48), supporting our hypothesis that IMST could potentially impact handgrip strength and dexterity. However, in this trial, any such changes in motor unit activation did not translate to changes in our physical function outcomes. Thus, although high-resistance IMST may improve some specific measures of physical performance, it may not have the ability to improve limb muscle function, such as occurs with conventional resistance exercise training.

Body Composition

We noted a 0.5 kg increase in thorax lean mass with high-resistance IMST which may be indicative of training-induced hypertrophy of the diaphragm and accessory respiratory muscles. Atrophy of the diaphragm occurs in animal models of aging (49) and age-associated changes in respiratory muscle function increase disease risk (50). While the DXA scans employed in this study do not allow us to confirm diaphragm hypertrophy, alternative IMST protocols have reported increases in diaphragm muscle mass in young healthy adults (51) and patients with chronic heart failure (52), after 4 to 8 weeks of training. Thus, it is possible that some degree of diaphragm hypertrophy occurred in our subjects, which may represent a beneficial adaptation in these midlife and older adults.

Similarly, we did not detect any changes in whole-body fat mass but noted a modest reduction in trunk fat (0.6 kg or ~4.5%). Trunk fat tends to increase with aging and is thought to contribute to increased cardiovascular and metabolic disease risk (53, 54). The reduction in trunk fat achieved in a group of non-obese midlife/older adults is noteworthy given that 30 resisted breaths per day presumably entails a rather minor increase in whole-body energy expenditure. This finding will need to be confirmed in larger subject populations and possibly with longer intervention durations. If prolonged high-resistance IMST can induce greater reductions in body fat, then IMST may become a helpful adjunct therapy to conventional aerobic exercise and caloric restriction in overweight and obese adults, a group at increased risk for morbidity and mortality who tend to demonstrate lower rates of adherence to aerobic exercise than their normal weight peers (55).

There were no changes in whole-body or regional bone mineral density. That no changes were observed is not surprising as bone mineral density is difficult to improve with aging and high-resistance IMST is non-weight bearing and does not produce impact forces, which are thought to be necessary to stimulate improvements in bone structure (56).

Experimental Considerations

This trial was powered to detect changes in casual systolic blood pressure; therefore, a limitation of this study is that we could only detect changes in within group comparisons and were underpowered to detect between-group differences in cardiorespiratory fitness-related outcomes. In addition, many of the changes we observed were modest and below the level of clinical significance. Another limitation is that we did not assess inspiratory capacity or maximal voluntary ventilation to confirm normal pulmonary function or assess changes in respiratory function in our participants. Without spirometry or serial inspiratory capacity maneuvers, we cannot determine how respiratory system capacity may have changed with IMST or evaluate changes in respiratory load and capacity during exercise. While we would not expect IMST to impact resting pulmonary function (57), we do not know the impact of IMST on mechanical ventilatory constraints. Older adults experience greater work of breathing, operate at higher lung volumes, and exhibit expiratory flow limitations relative to young adults (58); these are important outcomes that impact exercise hyperemia and would likely be related to improvements in exercise tolerance. We also did not measure respiratory and leg muscle fatigue after exercise or leg and respiratory muscle blood flow and mechanics during exercise; these measurements may have provided a greater mechanistic understanding of how IMST improves exercise tolerance.

The findings from the current clinical trial will need to be confirmed in a larger group of participants. Adaptations following a longer IMST treatment duration (12 and ~ 24 weeks) also would be of value, as would comparison with traditional aerobic exercise interventions; such a trial in postmenopausal women is currently underway (NCT05000515). Further investigation also is needed to fully understand the mechanisms through which high-resistance IMST increases exercise tolerance. Finally, our findings regarding plasma acylcarnitines should be considered hypothesis generating; further interrogation centered on pathways related to acylcarnitine synthesis and/or utilization are required.

CONCLUSIONS

Here, we demonstrate that in healthy midlife and older adults, high-resistance IMST improves exercise tolerance without changing cardiorespiratory fitness. We also observed improvements in ventilatory efficiency at VO2peak and in submaximal exercise economy, and shifts in acylcarnitine metabolism that may indicate changes in substrate availability and/or mitochondrial function. In addition, we found that high-resistance IMST may induce modest, region-specific changes in body composition, but does not improve select domains of physical function involving the peripheral musculature. Our results provide support for time-efficient, high-resistance IMST as a promising lifestyle intervention for improving exercise tolerance, including in groups with impaired whole-body exercise capacity.

Supplementary Material

Supplemental Data File (.doc, .tif, pdf, etc.)

Table S1. Maximal treadmill exercise: percent predicted values

Table S2. Relations between baseline plasma acylcarnitine levels and changes in treadmill exercise time

Table S3. Relations between changes in plasma acylcarnitine concentrations and changes in treadmill exercise time

Table S4. Responses to submaximal treadmill exercise using each participant’s lowest workload

Table S5. Physical function data: percent predicted values

Table S6. Lean body mass

Acknowledgements

The authors thank the staff of the University of Colorado Boulder Clinical and Translational Research Center for their technical assistance. This work was supported by National Institutes of Health awards R21AG061677, R01AG071506, R01AG065346, T32DK007135, UL1TR002535, P30CA046934, K01HL15336, K01DK115524, F31HL154782 and American Heart Association Award 18POST33990034.

Conflict of Interest and Funding Source:

This work was supported by National Institutes of Health awards R21AG061677, R01AG071506, R01AG065346, T32DK007135, UL1TR002535, P30CA046934, K01HL15336, K01DK115524, F31HL154782 and American Heart Association Award 18POST33990034. The authors have no conflicts of interest to disclose. The results of this study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of this study do not constitute endorsement of the American College of Sports Medicine.

Footnotes

Conflicts of Interest

The authors have no conflicts of interest to disclose. The results of this study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of this study do not constitute endorsement of the American College of Sports Medicine.

SUPPLEMENTAL DIGITAL CONTENT

SDC 1: MSSE-D-23–00284_supplemental digital content.docx

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Data File (.doc, .tif, pdf, etc.)

Table S1. Maximal treadmill exercise: percent predicted values

Table S2. Relations between baseline plasma acylcarnitine levels and changes in treadmill exercise time

Table S3. Relations between changes in plasma acylcarnitine concentrations and changes in treadmill exercise time

Table S4. Responses to submaximal treadmill exercise using each participant’s lowest workload

Table S5. Physical function data: percent predicted values

Table S6. Lean body mass

NIHMS1928269-supplement-Supplemental_Data_File___doc___tif__pdf__etc__.docx (43.8KB, docx)

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