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. 2025 Sep 16;126(2):965–977. doi: 10.1007/s00421-025-05966-0

Resistance exercise training similarly improves work efficiency and measured submaximal oxygen consumption during the 6-min walk test in healthy postmenopausal women and breast cancer survivors

Macarena Artigas-Arias 1,2, Rodrigo Muñoz-Cofre 3,4, Nicolás Vidal-Seguel 5, Andrea Alegría-Molina 6, Jorge Sapunar 2,4, Rui Curi 7,8,9, Gabriel Nasri Marzuca-Nassr 10,✉
PMCID: PMC12948827  PMID: 40954340

Abstract

Purpose

This exploratory study aimed to examine the potential effects of a 12-week progressive whole-body resistance exercise training (RET) program on measured submaximal oxygen consumption (submaximal VO2) and work efficiency during the 6-min walk test (6MWT) in healthy postmenopausal women and breast cancer survivors.

Methods

Twenty-four postmenopausal women (Healthy, HEA; 54 ± 3 years; BMI 26.6 ± 2.7 kg·m−2; n = 13 and breast cancer survivors, BCS; 52 ± 5 years; BMI 26.8 ± 2.1 kg·m−2; n = 11) completed a 12-week RET program. Participants were assessed using the 6MWT with a PNOE® metabolic analyzer before and after the intervention. Metabolic and respiratory parameters, including submaximal VO2 and work efficiency were measured. Data were analyzed using repeated measures ANOVA.

Results

Twelve-week RET improved the distance covered in the 6MWT by 10 ± 11% in the HEA group (from 586.6 ± 27.9 to 642.9 ± 35.9 m) and by 6 ± 16% in the BCS group (from 572.9 ± 62.6 to 604.7 ± 39.9 m) (P < 0.001; η2 = 0.54), with no significant differences between the groups (P = 0.175). There was an increase in RER (P < 0.001), ventilation (P = 0.043), and carbohydrate percentage (P < 0.001), along with a decrease in fat consumption percentage (P < 0.001), with no differences between groups (P > 0.05). After 12 weeks of RET, absolute submaximal VO2 decreased in both groups (P < 0.001), with no differences between them (P > 0.05). The maximum work rate increased (P < 0.001), with no differences between groups (P > 0.05). Work efficiency also improved over time (P < 0.05), with no differences between groups (P > 0.05).

Conclusion

As an exploratory analysis, these findings suggest that a 12-week RET program improved work efficiency and reduced measured submaximal VO2 during the 6MWT in both populations. The improvements were similar in healthy postmenopausal women and breast cancer survivors.

Trial registration number

NCT05690295.

Graphical abstract

graphic file with name 421_2025_5966_Figa_HTML.jpg

Supplementary Information

The online version contains supplementary material available at 10.1007/s00421-025-05966-0.

Keywords: Cancer, Resistance exercise training, Oxygen consumption, Work economy

Introduction

In recent decades, advancements in early diagnosis and personalized treatments for breast cancer have significantly increased the five-year survival rate, exceeding 90% in developed countries (Bray et al. 2024). However, postmenopausal breast cancer survivors face a heightened risk of musculoskeletal deconditioning, which negatively impacts their functional capacity and quality of life (Smoot et al. 2009). This deconditioning is attributed to factors such as prolonged physical inactivity and antineoplastic treatments, which lead to skeletal muscle atrophy, cancer-related fatigue, and a reduction in physical exercise capacity (Zhang et al. 2020; Kubo et al. 2017). Physiologically, this is reflected in a decrease in muscle fiber cross-sectional area, disruptions in protein balance, and mitochondrial dysfunction, affecting energy production and the maintenance of physical function (Artigas-Arias et al. 2024a).

Moreover, chemotherapy and endocrine therapy contribute to the selective loss of oxidative type I muscle fibers, capillary rarefaction, mitochondrial dysfunction, and increased intramuscular fat (myosteatosis), further compromising skeletal muscle oxidative capacity and peripheral oxygen extraction (Kirkham et al. 2021; Foulkes et al. 2024a).

The aging process further contributes to these changes, progressively increasing the oxygen cost of daily activities through declines in muscle and mitochondrial function (Peterson et al. 2012; Woo et al. 2006). Work efficiency, the ratio between mechanical output and energy expenditure, decreases with age and disease (Layec et al. 2015; Pedrinolla et al. 2023). This extra energy demand leads to higher oxygen consumption, making daily tasks more physically demanding (Yang et al. 2021). These alterations result in reduced exercise tolerance and higher metabolic cost during submaximal activities, which are commonly observed in both older adults and cancer survivors (Guigni et al. 2018; Haykowsky et al. 2022; Conley et al. 2000; Hunter et al. 2002).

In this context, tools to assess cardiorespiratory functional capacity during submaximal activities are essential. Cardiorespiratory capacity is often measured as “maximal oxygen consumption (VO2 max)” which reflects the efficiency of the circulatory and respiratory systems in delivering oxygen to the muscles during exercise and can be directly measured through maximal exercise test. While VO₂ max requires the identification of a plateau in oxygen consumption, measured “submaximal oxygen consumption (submaximal VO₂)” represents the highest oxygen consumption value obtained during submaximal protocol, such as the six-minute walk test (6MWT), and is commonly used in oncology (But-Hadzic et al. 2021; Whipp and Wasserman 1972). Both are key indicators of physical fitness (Snell et al. 2007). The 6MWT is a widely used method that evaluates functional capacity in older adults (Enright et al. 2003) and breast cancer survivors by measuring walking distance and associated physiological responses (Galiano-Castillo et al. 2016; Ying et al. 2020).

In postmenopausal breast cancer survivors (Avis and Deimling 2008; Keating et al. 2005) peripheral limitations such as skeletal muscle atrophy, reduced capillarization, and impaired mitochondrial function hinder oxygen extraction at the muscle level (Kirkham et al. 2021; Avis and Deimling 2008; Keating et al. 2005). This results in alterations in VO₂ and increased energetic demands during submaximal exercise, contributing to impaired functional performance (Kirkham et al. 2021; Beaudry et al. 2020).

Evidence suggests that older adults who engage in structured physical activity for at least a year demonstrate greater work efficiency compared to their sedentary counterparts (Broskey et al. 2015). This improvement in efficiency may be explained by an increase in the number of mitochondria in skeletal muscle and a heightened capacity to generate energy in the form of adenosine triphosphate (ATP)(Santanasto et al. 2015).

Resistance exercise training (RET) can enhance work efficiency by promoting mitochondrial and metabolic adaptation that lowers the oxygen cost of physical tasks, thereby saving energy during submaximal activities (Vikmoen and Rønnestad 2021; Vikmoen et al. 2016). A recent study in untrained young men demonstrated that RET reduces oxygen consumption during submaximal exercise, with improvements attributed to changes in muscle fiber composition, enhanced metabolic pathways, and better neuromuscular coordination (Barrett-O’Keefe et al. 2012). The findings indicate the physiological basis by which RET improves functional performance (Barrett-O’Keefe et al. 2012).

In clinical populations, such as women with breast cancer, similar mechanisms may be especially relevant. For example, Mijwel et al. (2018) showed that women undergoing adjuvant chemotherapy experienced a decline in oxidative muscle fibers, citrate synthase activity, and capillarization due to treatment and physical inactivity. However, a 16-week intervention combining high-intensity aerobic training with RET during chemotherapy effectively attenuated mitochondrial dysfunction and preserved muscle characteristics that are critical for metabolic efficiency (Mijwel et al. 2018).

Despite promising evidence, the adaptive response to RET may be diminished in postmenopausal breast cancer survivors due to age- and treatment-related alterations in skeletal muscle, such as impaired mitochondrial biogenesis, myosteatosis, and reduced muscle quality. These changes could limit the effectiveness of conventional exercise protocols. Yet, few studies have evaluated whether RET improves work efficiency and oxygen economy during submaximal tasks in this population, as most existing data derive from healthy men, and trained individuals, highlighting a critical gap in the literature.

Therefore, this exploratory study aimed to examine the effects of a 12-week progressive whole-body RET program on work efficiency and measured submaximal VO2 during the 6MWT in healthy postmenopausal women compared to postmenopausal breast cancer survivors. We hypothesized that RET may lead to improvements in both parameters by enhancing neuromuscular coordination and peripheral oxygen utilization, although the magnitude of these improvements may differ between groups due to treatment-related muscle deconditioning in the cancer survivor participants. In addition, a secondary aim was to explore whether RET modulates substrate utilization patterns specifically carbohydrate and fat oxidation during submaximal exercise, as an indicator of metabolic adaptation in response to training.

Methods

Participants

This study involved 24 participants who completed the research and were divided into two groups: healthy postmenopausal women (HEA, 54 ± 3 years, BMI 26.6 ± 2.7 kg/m2, n = 13) and postmenopausal breast cancer survivors (BCS, 52 ± 5 years, BMI 26.8 ± 2.15 kg/m2, n = 11). This research is part of a project designed to compare the effects of a 12-week progressive RET program on skeletal muscle mass, muscle strength, and physical performance in healthy postmenopausal women versus postmenopausal breast cancer survivors (Artigas-Arias et al. 2024b). The study was approved by the Scientific Ethics Committee of the University of La Frontera, Temuco, Chile (registration No. 004_23) in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants. Inclusion criteria required participants to be healthy postmenopausal women or breast cancer survivors who had completed primary antineoplastic treatment ≥ 6 months before, aged between 45 and 59 years, with a BMI between 18.5 and 30 kg/m2, and willing to take part in the study.

Before enrollment, participants were provided with a thorough explanation of the study protocols, underwent a routine medical exam, and completed a general health questionnaire to ensure they met the suitability criteria. Exclusion criteria included cardiovascular diseases incompatible with physical exercise, comorbidities affecting body mobility and muscle metabolism, smoking, use of nutritional supplements (leucine, glutamine, casein, whey protein, fatty acids, and creatine), and use of estrogen replacement therapy.

Both groups participated in the 12-week progressive whole-body RET program and were evaluated in two separate tests (test 1, PRE and test 2, POST), which were conducted 48 h before the first session and 48 h after the last training session. Participants were instructed not to consume alcohol or engage in intense physical activity for 2 days prior to each test day.

Experimental design

This non-randomized quasi-experimental study involved participants undergoing an initial comprehensive interview and receiving medical clearance to confirm their ability to complete a 6MWT protocol and the progressive RET program.

Blood pressure, heart rate and body weight

Before each 6MWT, blood pressure, resting heart rate (HR), and body weight were assessed. Blood pressure (BP) was measured with an OMRON® (Japan) digital monitor on the forearm opposite to the mastectomy side. Heart rate was determined using a POLAR® (Finland) monitor, and body weight was measured with the OMRON® HBF-514C (Japan) electrical bioimpedance device.

Six-minute walk test (6MWT)

The 6MWT was conducted following the guidelines of the American Thoracic Society (ATS) in a 30-m-long corridor, with standardized verbal encouragement provided throughout (Committee and on Proficiency Standards for Clinical Pulmonary Function Laboratories 2002). An experienced evaluator performed all measurements. After the test, participants entered a recovery phase, where they rested in a chair. Upon test completion, the exact point at which the participant stopped was marked, and the evaluator measured the remaining distance from the farthest point to stopping point using a tape measure. This value was then added to the total distance covered to ensure an accurate calculation. Before and after the test, HR, BP, and perceived exertion according to the Borg scale were recorded.

Cardiopulmonary exercise testing

Cardiopulmonary exercise testing was conducted using the PNOE metabolic analyzer (ENDO Medical, Palo Alto, CA), a portable and wireless device that directly measures oxygen exchange kinetics on a breath-by-breath basis during the 6MWT (Tsekouras et al. 2019).

Heart rate was continuously monitored using a POLAR® ECG-activated belt (Finland). Key respiratory variables, including measured submaximal oxygen consumption (submaximal VO₂), carbon dioxide production (VCO₂), tidal volume, and respiratory rate, were assessed through a face mask equipped with a flow sensor and gas analyzer, which featured a dead space of less than 70 ml to ensure minimal interference with gas exchange accuracy. The participant wore data storage and transfer units secured in a dedicated harness. Real-time breath-by-breath data was transmitted to a laptop, enabling continuous monitoring throughout the test. The additional equipment weight (approximately 800 g) was lightweight enough that it did not impact the participant’s distance covered (Tueller et al. 2010).

Calculation of maximal workload and work efficiency

The maximal workload (W peak) was calculated from the 6MWT using the equation by Luxton N. et al. (2008), which was previously validated in a clinic population with stable conditions. This formula is as follows (Luxton et al. 2008): Wpeak=103.217+30.50∗sexF=0,M=1+-1.613∗agey+0.002∗6MWT∗weightm·kg-1.

Subsequently, work efficiency was determined using the formula: Wpeak/(submaximalVO2-VO2rest)∗100.

Both oxygen consumption (submaximal VO₂ and VO2 rest) and workload values were converted to kilojoules as previously described (Hoff et al. 1999) and expressed as percentage changes.

Resistance exercise training

Participants from both groups underwent a 12-week progressive whole-body RET program consisting of 36 individually monitored training sessions. Training sessions were conducted three times per week on non-consecutive days (Monday, Wednesday, and Friday) starting with a warm-up, followed by five sets of exercises for the lower body using leg press and leg extension machines (TuffStuff Fitness International, California, USA). For the upper body, participants performed three sets each of chest press, triceps extension, and horizontal rowing exercises (Fit Tech, Portugal). Rest intervals between sets lasted 2 min. The workload ranged from 60 to 80% of the participants one-repetition maximum (1RM). The 1RM was reassessed at the sixth week of the intervention to adjust workloads as previously reported (Marzuca-Nassr et al. 2024).

Sample size

The sample size in this study was initially calculated for the primary variable of the previously published research (Artigas-Arias et al. 2024b). However, to ensure that the number of participants was optimal for the post hoc statistical analysis of work efficiency, a new sample size calculation was performed. Since no previous studies have examined this variable in healthy postmenopausal women or breast cancer survivors, data from trained male cyclists were considered as a reference (Barrett-O’Keefe et al. 2012). In that study, an increase in work efficiency from 22 ± 1% to 27 ± 2% was observed, with an effect size of 0.95. Considering a significance level of 0.05 and a power of 95%, the calculation determined that 8 participants per group were required. To account for a 20% dropout rate, a minimum of 10 participants per group was estimated. This adjustment ensures the statistical validity of the secondary analyses and strengthens the robustness of the findings.

Statistical analysis

The data showed a normal distribution according to the Shapiro–Wilk test and are therefore presented as mean ± standard deviation (SD). Baseline characteristics between the groups were compared using an independent sample t-test. Pre- and post-intervention data were analyzed using repeated measures ANOVA, with time (PRE versus POST) as a within-subject factor and group (HEA versus BCS) as a between-subject factor. Partial eta squared was used to estimate effect sizes from ANOVA calculations and is represented as η2, where 0.01 indicates a small effect size, 0.06 a medium effect size, and 0.134 or higher a large effect size. Significance was set at P < 0.05. After conducting the repeated measures ANOVA, when a statistically significant time effect was detected, changes (deltas) in the study variables between the groups were compared using an independent sample t-test. This analysis enabled the evaluation of whether both groups experienced similar benefits following the RET program. All statistical tests were performed using SPSS software (IBM SPSS Statistics, v. 21) and figures were created using GraphPad Prism 8.2 software (San Diego, CA).

Results

Baseline Characteristics

Baseline characteristics of the participants are detailed in Table 1. All variables showed no significant baseline differences between the two groups (P > 0.05). All participants completed the 6MWT protocol and RET sessions without complications.

Table 1.

Participants characteristics

HEA (n = 13) BCS (n = 11) P-value
Age (y) 54 ± 3 52 ± 5 0.155
Weight (kg) 63.8 ± 9.2 67.1 ± 7.2 0.175
Height (m) 1.51 ± 14.4 1.58 ± 7.2 0.068
BMI (kg.m2) 26.6 ± 2.7 26.8 ± 2.1 0.539
HR (bpm) 71.2 ± 11.3 73.3 ± 6.3 0.284
SBP (mm Hg) 115.5 ± 11.8 114.2 ± 9.8 0.389
DBP (mm Hg) 79.8 ± 10.7 78.5 ± 7.1 0.365
6MWT distance (m) 586.6 ± 27.9 572.9 ± 62.6 0.514
Submaximal VO2 (ml·kg−1·min−1) 30.7 ± 6.42 29.8 ± 8.3 0.757
Submaximal VO2 (L· min−1) 1.9 ± 0.4 1.9 ± 0.5 0.857
CO2 (L· min−1) 1.7 ± 0.3 1.8 ± 0.5 0.500
Peak work rate (W) 95.6 ± 14 91.6 ± 13 0.375
VE (L/min) 63.6 ± 8.5 62.7 ± 11.8 0.843
RER 0.96 ± 0.14 0.97 ± 0.9 0.801
CHO (Kcal) 29.1 ± 14.2 31.6 ± 15.1 0.686
CHO (%) 61.2 ± 26.5 62.9 ± 21.1 0.862
FAT (Kcal) 21.1 ± 16.3 18.5 ± 10.1 0.653
FAT (%) 40.2 ± 27.1 37.1 ± 21.1 0.762
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Data presented as mean ± SD. HEA Postmenopausal healthy group, BCS Postmenopausal breast cancer survivors group, BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure, HR heart rate, bpm beats per minute, 6MWT 6-Minute Walk Test, VO2 Oxygen Consumption, VE Minute Ventilation, RER Respiratory Exchange Ratio, CHO Carbohydrates substrate, FAT Fat substrate. Data were analyzed using independent samples t-tests

Metabolic and respiratory parameters during the 6MWT

Twelve-week RET improved the distance covered in the 6MWT by 10 ± 11% (from 586.6 ± 27.9 to 642.9 ± 35.9 m) and by 6 ± 16% (from 572.9 ± 62.6 to 604.7 ± 39.9 m) in HEA and BCS, respectively (time effect: P < 0.001; η2 = 0.54), with no differences between groups (Time × Group: P = 0.175) (Table 2). Relative submaximal VO2 decreased in both groups (from 30.7 ± 6.4 to 28.5 ± 4.2 ml/kg−1/min−1 in HEA and from 29.8 ± 8.3 to 28.4 ± 6.2 ml/kg−1/min−1 in BCS) (Time × Group: P = 0.711). Additionally, after 12 weeks of RET, RER increased in both groups (P < 0.001), as did ventilation (VE) (P = 0.043) and the percentage of carbohydrates (CHO%) (P < 0.001), while the percentage of fat consumption (FAT%) decreased significantly (P < 0.001). No differences were found between the groups in all measured variables (Time × Group: all P ≥ 0.307).

Table 2.

Metabolic and respiratory parameters during the 6MWT before and after 12 weeks of resistance exercise training

HEA
(n = 13)		 BCS
(n = 11)		 STATISTICS
(P-value)
PRE POST PRE POST Time Time × Group Group
6MWT (meters) 586.6 ± 27.9 642.9 ± 35.9 572.9 ± 62.6 604.7 ± 39.9  < 0.001 0.175 0.101
Submaximal VO2 (ml·kg−1·min−1) 30.7 ± 6.4 28.5 ± 4.2 29.8 ± 8.3 28.4 ± 6.2 0.116 0.711 0.825
CO2 absolute (L/min) 1.73 ± 0.3 1.89 ± 0.4 1.85 ± 0.5 1.97 ± 0.5 0.111 0.832 0.529
VE (L/min) 63.6 ± 8.5 70.5 ± 13.8 62.7 ± 11.8 67.2 ± 13.2 0.043 0.646 0.621
RER 0.96 ± 0.14 1.08 ± 0.07 0.97 ± 0.09 1.06 ± 0.06  < 0.001 0.535 0.919
CHO (Kcal) 29.1 ± 14.2 39.5 ± 11.3 31.6 ± 15.1 43.4 ± 17.2 0.007 0.844 0.495
CHO (%) 61.2 ± 26.5 84.1 ± 9.6 62.9 ± 21.1 76.8 ± 15.9  < 0.001 0.326 0.682
FAT (Kcal) 21.1 ± 16.3 7.5 ± 3.6 18.5 ± 10.1 10.6 ± 5.2  < 0.001 0.307 0.935
FAT (%) 40.2 ± 27.1 15.9 ± 9.6 37.1 ± 21.1 19.5 ± 11.3  < 0.001 0.484 0.973
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Data presented as mean ± SD. HEA Postmenopausal healthy group, BCS Postmenopausal breast cancer survivors group, 6MWT 6-Minute Walk Test, VO2 Oxygen Consumption, VE Minute Ventilation, RER Respiratory Exchange Ratio, CHO Carbohydrates substrate, FAT Fat substrate. Data were analyzed using repeated measures ANOVA (time x group). Bold values indicate statistically significant differences (P < 0.05)

Physiological performance parameters during the 6MWT

After twelve week RET, absolute submaximal VO2 decreased by 8 ± 4% (from 1.94 ± 0.4 to 1.80 ± 0.4 L/min) in the HEA group and by 4 ± 2% (from 1.98 ± 0.5 to 1.89 ± 0.5 L/min) in the BCS group (time effect: P < 0.001; η2 = 0.49), with no significant differences between groups (Time × Group interaction: P = 0.174; Group effect: P = 0.715; Fig. 1a). Percentage differences between groups were also not significant (independent T-test: P = 0.198; Fig. 1b).

Fig.1.

Fig.1

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Submaximal VO2 during the 6MWT A Measured submaximal oxygen consumption (Submaximal VO2) before and after 12 weeks of resistance exercise training. B Percentage change in submaximal VO2 following 12-week RET program in healthy postmenopausal women, (n=13) and breast cancer survivors,(n=11) groups. Data were analyzed using repeated measures ANOVA (Time X Group) (A) and independent t test (B), not observing interaction or differences between the groups, respectively. The effect size for the main effect of time on submaximal VO₂ was large (η² = 0.496).

The maximum work rate also increased significantly, rising by 8 ± 5% (from 90.6 ± 13.1 to 97.7 ± 12.9 W) in HEA and by 5 ± 7% (from 95.6 ± 13.9 to 100.5 ± 14.6 W) in BCS (time effect: P < 0.001; η2 = 0.61), with no differences between groups (Time × Group interaction: P = 0.296; Group effect: P = 0.482; Fig. 2a). Percentage differences between groups were not statistically significant (independent T-test: P = 0.288; Fig. 2b).

Fig. 2.

Fig. 2

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Peak Work Rate and Work Efficiency during the 6MWT. A Peak Work Rate; C Work Efficiency before and after 12-week RET program. Percentage change in B. Peak Work Rate; D Work Efficiency following 12-week RET program in healthy postmenopausal women (HEA, n=13) and breast cancer survivors (BCS, n=11) groups. Data were analyzed using repeated measures ANOVA (Time X Group) (A and C) and independent t test (B and D), not observing interaction or differences between the groups, respectively. The effect sizes for the main effect of time were large for both variables (η² = 0.613).

Similarly, work efficiency improved over time, increasing by 18 ± 7% (from 4.8 ± 0.8 to 5.5 ± 0.8%) in HEA and by 11 ± 7% (from 5.1 ± 1.4 to 5.5 ± 1.3%) in BCS (time effect: P = 0.048; η2 = 0.17). No differences were observed between groups for any of the measured variables (Time × Group interaction: P = 0.520; Group effect: P = 0.686; Fig. 2c). No significant differences were observed in the percentage differences between groups (independent T-test: P = 0.485; Fig. 2d).

Discussion

This exploratory study examined the effects of a 12-week progressive RET program on measured submaximal VO2 and work efficiency during the 6MWT in healthy postmenopausal women and breast cancer survivors. The results showed significant improvements in functional capacity, as evidenced by an increase in distance covered during the 6MWT. Metabolic parameters also showed progress, with increases in the respiratory exchange ratio (RER) and a greater utilization of carbohydrates (CHO) as the primary energy source. Additionally, respiratory parameters improved including an increase in ventilation (VE), alongside enhanced physiological performance, reflected in greater work efficiency and reduced oxygen demand during the submaximal test.

In accordance with previous studies, our research demonstrated a significant improvement in the distance covered during the 6MWT after 12 weeks of RET. Healthy postmenopausal women increased their distance by approximately 10%, while breast cancer survivors improved by around 6%, with no significant differences between the groups. These findings are consistent with existing literature, which indicates that structured exercise programs can substantially enhance functional capacity in breast cancer survivors (Ficarra et al. 2022). This improvement is particularly relevant, as other studies suggest that cancer leaves physical sequelae that impact functionality and may accelerate the aging process (Hurria et al. 2016). Moreover, these findings highlight the importance of implementing exercise programs, such as the one proposed in this study, that support medium- and long-term recovery in breast cancer survivors, like the participants in this research (Artigas-Arias et al. 2024b), and contribute to preserving health in this vulnerable population (Smith-Turchyn et al. 2024; Qiu et al. 2023).

Although the 6MWT was performed only once at baseline and once post-intervention, this decision was supported by strong evidence of its reliability in cancer populations. In a validation study by Schmidt et al. (2013), the 6MWT was administered twice, 2 to 7 days apart, in patients with various cancer types (including 38% with breast cancer). The results showed excellent test–retest reliability, with an intraclass correlation coefficient of 0.93 and a coefficient of variation of 3%. Although participants walked on average 3.1% farther on the second test, only changes greater than 5.2% were considered meaningful (Schmidt et al. 2013). In our study, post-intervention improvements exceeded this threshold in both groups (+ 10% in healthy women and + 6% in breast cancer survivors), supporting the interpretation of true physiological adaptations rather than measurement error or familiarization effects.

This study showed a significant increase in the RER and the percentage of carbohydrate use (CHO%) after 12 weeks of RET. These findings align with previous research suggesting that RET may induce a metabolic shift towards greater carbohydrate oxidation during submaximal exercise (Consitt et al. 2019). Lippi et al. (2022) observed that RET enhances mitochondrial density and dynamics, increasing the capacity to oxidize carbohydrates and efficiently produce energy in older adults (Lippi et al. 2022). Similarly, Manfredi et al. (2013) observed that these metabolic adaptations not only optimize glucose utilization during exercise, but may also reduce insulin resistance, a crucial factor for maintaining metabolic health and efficiency in postmenopausal women (Manfredi et al. 2013). In this same sense, another study reports that 16 weeks of RET causes a greater reserve of muscle glycogen (60.3 ± 3.9 to 79.1 ± 5.0 mmol of glucose/kg) in older people with type 2 diabetes (Castaneda et al. 2002). For this reason, the higher percentage of CHO oxidation observed in our results can be explained by the post-intervention muscle adaptation. Although no study has directly evaluated changes in substrate utilization in breast cancer survivors undergoing RET, recent findings indicate that women with breast cancer show alternate muscle metabolism, including lower carbohydrate oxidation during exercise compared to healthy controls (Tosti et al. 2011). This metabolic inflexibility may contribute to increased perceived exertion and reduce functional performance, particularly during submaximal tasks.

Additionally, Groennebaek et al. (2017) reported that RET not only increases muscle mass and strength, but also alters energy metabolism, promoting a greater reliance on carbohydrates as an energy source during exercise (Groennebaek and Vissing 2017). The reduction in fat use as an energy substrate may be attributed to increased glycogen availability and utilization, a phenomenon supported by studies such as Porter et al. (2015), which highlight greater glucose utilization efficiency following an RET regimen (Porter et al. 2015).

Studies have demonstrated improvements in work efficiency and a reduction in oxygen consumption following RET across various populations. Similarly, Hoff et al. (1999) observed that nine weeks of maximal strength training increased work efficiency by 22 ± 0.1% in young female cross-country skiers (Hoff et al. 1999). Likewise, Zachary et al. (2012) found that eight weeks of maximal strength training in trained young men reduced oxygen consumption by 9 ± 0.2% during a submaximal activity on a cycle ergometer (Barrett-O’Keefe et al. 2012). In our study, we observed an increase in work efficiency of 18 ± 7% in the HEA group and 11 ± 7% in the BCS group, as well as a reduction in submaximal VO2 during a submaximal walking test. These findings gain further relevance considering that aging and cancer-related treatments exacerbate musculoskeletal and mitochondrial dysfunction, increasing the oxygen cost required for daily activities. Evidence suggests that older adults expend ~ 8% more oxygen to perform everyday tasks, such as walking, compared to younger individuals, due to impaired energy efficiency (Layec et al. 2015). Therefore, the observed 8–11% reduction in measured submaximal VO₂ after RET in both groups may reflect a clinically meaningful enhancement in muscle efficiency and energy economy during functional activities. This improvement may contribute to reduced fatigue, increased mobility, and better preservation of independence in postmenopausal and clinical populations.

Moreover, the 8–11% reduction in submaximal VO₂ observed in both groups appears to be clinically meaningful. While the minimal important difference (MID) of ≥ 1.65 mL/kg−1/min−1 proposed by Foulkes et al. (2024) refers to VO₂ max after a 12-month intervention, the average reduction observed in our study (–7.19 to 4.7 mL/kg−1/min−1) among breast cancer survivors clearly exceeds this benchmark (Foulkes et al. 2024b). The reliability of the relative submaximal oxygen consumption measurement was confirmed with an intraclass correlation coefficient (ICC) of 0.987 and a minimal detectable change at 95% confidence (MDC95) of 0.0179 L/min. Notably, the reduction observed in the BCS group (–0.05 L/min) clearly surpassed this MDC95 threshold. These results support the interpretation that reductions in submaximal VO₂ represent genuine physiological adaptations rather than measurement error.

As a sensitivity analysis, we compared the Luxton equation with two alternative workload estimation models, Hill et al. (2008) and Piaggi et al. (2024), both developed from 6MWT data in clinical populations with chronic obstructive pulmonary disease and congestive heart failure, respectively. All three equations demonstrated significant post-intervention increases in estimated peak workload (W peak) and showed similar trends across groups, supporting the robustness of our findings. Although absolute workload values differed slightly between equations—likely due to differences in the original calibration cohorts—the consistency in the direction and magnitude of change reinforces confidence in our results.

Although direct Cardiopulmonary Exercise Testing (CPET) validation of the Luxton workload equation was not feasible in this cohort, its use provides a reasonable approximation of workload estimation based on 6MWT performance. Given that the equation was originally developed in patients with Chronic Obstructive Pulmonary Disease (COPD), future studies should directly validate 6MWT-derived workload estimations against CPET in breast cancer survivors to confirm its applicability in this population.

Differences in work efficiency between studies may be attributed to variations in population characteristics and training types (Vikmoen and Rønnestad 2021; Hoff et al. 1999).

While Hoff et al. (1999) focused on young, trained women, our approach was directed towards untrained postmenopausal women, with and without a history of breast cancer, who generally exhibit lower baseline work efficiency due to aging and physical inactivity (Woo et al. 2006; Martin et al. 1992). Likewise, discrepancies in submaximal oxygen consumption can be explained by the type of test used. Submaximal cycling is known to generate higher levels of arterial lactate than submaximal steady-state walking, indicating a greater reliance on anaerobic metabolism during cycling (Ward et al. 2021; Vonbank et al. 2020). This can increase oxygen consumption and reduce the accuracy of aerobic efficiency assessment. These factors support the idea that submaximal walking, as employed in our study, may better reflect aerobic adaptations and efficiency in daily activities, thus reinforcing the benefits observed in our sample following resistance training (Ortega and Farley 2007).

Although the reasons for these improvements in work efficiency and reductions in oxygen consumption are not entirely clear, we hypothesized that RET may achieve these effects primarily through adaptations in skeletal muscle, as suggested by previous mechanistic studies (Barrett-O’Keefe et al. 2012). Potential mechanisms include a shift in muscle fiber composition, with a reduction in type IIb fibers and an increase in type IIa fibers, which decreases metabolic cost and improves contractile efficiency (Adams et al. 1993; Pringle et al. 2003). Another plausible mechanism is to reduce motor unit recruitment, as less muscle may be required to lift a given load, resulting in decreased metabolic demand (Hill 1922). Finally, improvements in neuromuscular coordination or the kinetics of force development may contribute to greater mechanical efficiency or metabolic expenditure (Russ et al. 2002). However, their interpretations remain hypothetical and should be interpreted cautiously, as our study did not include direct assessments such as muscle biopsies or electromyographic analyses.

Despite the observed improvements, the study has certain limitations. Although the sample size was relatively small, an optimal number of participants per group was included, calculated through a Post Hoc statistical power analysis, which showed 95% power to detect the pre-established difference in maximal oxygen consumption between groups, even considering a possible dropout rate of up to 30% of participants. Additionally, 6MWT was performed only once at each evaluation point; the decision was based on prior reliability data, as discussed above. Nonetheless, future studies may consider familiarization trials to reduce residual variability. Although the 6MWT is a submaximal measure that effectively represents daily activities, it may not fully capture exercise adaptations compared to more precise methods, such as cardiopulmonary exercise testing). However, the incorporation of a metabolic analysis device in the 6MWT allowed for a comprehensive and innovative study of the effects of RET on metabolic and respiratory demands during a common submaximal activity, such as walking. Moreover, while the Luxton equation used to estimate maximal workload and work efficiency was originally validated in patients with COPD, emerging evidence suggests that breast cancer survivors particularly—those exposed to cardiotoxic therapies share physiological similarities with individuals with heart failure or COPD (Haykowsky et al. 2022). These include impaired aerobic capacity, altered peripheral oxygen extraction, and elevated ventilatory demands during submaximal activities.

In this context, applying a clinically validated functional equation to estimate maximal workload may still yield meaningful insights in breast cancer survivors, especially when interpreted alongside metabolic data, as done in the present study.

Lastly, this study did not directly investigate physiological muscle adaptations or their relationship with motor unit recruitment, which led us to base our arguments on findings from previous studies. The absence of muscle biopsies represents a significant methodological limitation, as it prevents direct evaluation of the cellular and structural adaptations induced by RET. These results are hypothesis generating and should be interpreted within the context of an exploratory study, which provides valuable preliminary evidence to guide future research directions and the design of large confirmatory trials. Future trials with larger sample sizes and direct CPET validation will be essential to verify the robustness of our 6MWT derived workload estimations and clarify the underlying physiological adaptations.

In conclusion, this exploratory study suggests that a 12-week program of progressive whole-body RET improved work efficiency and reduced measured submaximal oxygen consumption during submaximal exercise in postmenopausal women. These improvements were observed in both healthy postmenopausal women and breast cancer survivors, with no differences between the groups. These preliminary findings support the feasibility and potential of RET as a strategy to improve metabolic and physical function in postmenopausal women, with or without a history of breast cancer. Confirmatory studies are needed to validate these results and better understand the underlying mechanisms.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 KB) (19.4KB, docx)

Acknowledgements

We greatly appreciate the assistance of the following colleagues in the execution of the experiments: Mariel Sánchez, Valentina Barra, and Ignacio Vilar-Bertolotto (all part of physiotherapy graduation programme, Universidad de La Frontera) and the technical expertise from Juan Carranza-Leiva, Alexis Sepúlveda-Lara, Kaio Fernando Vitzel, Nolberto Huard and Luis A Salazar.

Abbreviations

6MWT

Six-minute walk test

1RM

One repetition maximum

ATP

Adenosine triphosphate

BCS

Breast cancer survivors

BMI

Body mass index

BP

Blood pressure

HEA

Healthy postmenopausal woman

HR

Heart rate

RET

Resistance exercise training

VCO2

Carbon dioxide production

VE

Ventilation (minute ventilation)

VO₂

Measured oxygen consumption

VO₂max

Measured maximal oxygen consumption

Submaximal VO2

Measured submaximal oxygen consumption

W Peak

Maximal workload

Author contributions

All authors meet the international committee of Medical Journal Editors criteria for authorship for this article and contributed substantially to the study concept and design: all authors; acquisition of data: MA-A, RC-M, NV-S, AA-M, JS, RC, and GN-MN; statistical analysis: MA-A, RC, and GN-MN, analysis and interpretation of data: MA-A, RC-M and GN-MN; drafting of manuscript: all authors. All authors read and approved the final version of the manuscript.

Funding

This research was carried out using financial support from the Dirección de Investigación (DIUFRO) of Universidad de La Frontera, Chile (FPP22-0016) and Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil (FAPESP Brazil, N°2022/09341–4). M.A-A, and N.V-S. were funded by the National Research and Development Agency (ANID)/Human Capital Sub-directorate/National Doctorate Scholarships 2021—21211236 and 2022—21220848, respectively. R. C. is the recipient of a CNPq scholarship.

Declarations

Conflicts of interest

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Data availability

The data associated with the paper are not publicly available but are available from the corresponding author on reasonable request.

Footnotes

Publisher's Note

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Supplementary Materials

Supplementary file1 (DOCX 19 KB) (19.4KB, docx)

Data Availability Statement

The data associated with the paper are not publicly available but are available from the corresponding author on reasonable request.

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