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We examined the effect of endurance training on energy substrate partitioning during rest and exercise in postmenopausal women. Ten healthy sedentary (55 ± 1 yr) subjects completed 12 weeks of endurance exercise training on a cycle ergometer [5 days/wk, 1 h/day, 65% peak oxygen consumption (VO2 peak)]. Whole-body energy substrate oxidation was determined by indirect calorimetry during 90 minutes of rest and 60 minutes of cycle ergometer exercise. Subjects were studied at 65% VO2peak before training and after training at the same absolute exercise intensity (same absolute workload as 65% of pretraining VO2peak) and same relative exercise intensity (65% of post-training VO2peak). After training, VO2peak increased by 16.3 ± 3.9% and resting heart rate decreased by 4 bpm (p < 0.05). During exercise at same absolute intensity, mean arterial pressure decreased by 8 mmHg (p < 0.05), heart rate decreased by 19 bpm (p < 0.05), energy derived from carbohydrate decreased 9.6%, and the energy derived from lipid increased by 9.2% (p < 0.05). Lactate concentration was lower at the same absolute and relative exercise intensities (p < 0.05). Changes in substrate partitioning during exercise were accomplished without changes in dietary composition, body weight, or body composition. We conclude that endurance training in healthy postmenopausal women that remain in energy balance, results in many of the classic cardio-pulmonary training effects, decreases the reliance on carbohydrate and increases lipid oxidation during a given submaximal exercise task without a reduction in body weight.
Previous studies examining the effects of endurance training have shown that while both younger men and women can increase their cardiorespiratory capacity after training, younger women oxidize proportionately more lipid and less carbohydrate during exercise (14). While studies on young women (14) have demonstrated that endurance training increases cardiorespiratory capacity and decreases carbohydrate oxidation during exercise tasks of given absolute and relative exercise intensities, it is unclear whether the same training responses occur in postmenopausal women. Age-related changes in body composition and a decline in aerobic capacity (26) may dampen the cardiorespiratory training response in postmenopausal women relative to premenopausal levels. As well, the decline in estrogen levels at menopause alters the hormonal milieu and may have a significant effect on altering energy substrate partitioning (%CHO/%lipid) during rest and exercise. In young women estrogen has been shown to decrease carbohydrate oxidation during exercise (7, 9, 14) and can alter glucose metabolism by decreasing gluconeogenesis, glycogenolysis, and insulin-binding capacity thereby shifting the substrate partitioning toward lipid metabolism (4). Therefore, the decline in estrogen at menopause may lead to an increased reliance on carbohydrate and decreased reliance on lipid during rest and exercise. Endurance training may help to override the effects of estrogen withdrawal on substrate partitioning by increasing lipid oxidation.
To date most studies examining the effects of endurance training on substrate partitioning in older individuals have been of a mixed gender study design (28, 29) so it is unclear whether the effect of endurance training on metabolism is the same in older men and women. Sial et al. found that compared to young subjects, fat oxidation during exercise was significantly lower in older (age 73 ± 2 yr) than young subjects (age 26 ± 2 yr) during 60 minutes of cycle ergometer exercise performed at either the same absolute or relative exercise intensity (28). However, Sial et al. found that 16 weeks of endurance training (age 74 ± 2 yr, 3 men and 3 women) caused an increase in fat oxidation and a decrease in carbohydrate oxidation in elderly persons at the same absolute exercise intensity (29). A pre- vs. post-training comparison at similar relative exercise intensities was not reported. Those findings can be interpreted to mean that endurance training may be capable of overriding the negative effects of estrogen withdrawal on substrate partitioning. However, because of the mixed gender study design of these previous studies (28, 29), the effects of endurance training on postmenopausal women remains unclear.
To evaluate the idea that exercise training would override the effects of menopause and estrogen withdrawal on energy substrate partitioning and cardiovascular fitness during rest and exercise, we determined the effects of 12 weeks of moderate intensity endurance training in sedentary, but otherwise healthy postmenopausal women. We predicted that exercise training would enhance lipid oxidation during physical activity and increase cardiovascular fitness in the absence of weight loss.
Ten healthy, nonsmoking, weight-stable postmenopausal women (55 ± 0.61 yr) were recruited from the University of California campus and the surrounding community by posted notices and internet advertisements. The women were considered to be postmenopausal if they had not menstruated for at least a year, and their plasma follicle-stimulating hormone (FSH) levels were greater than 30 mIU/mL. Subjects were considered sedentary if they participated in < 2h of regular strenuous activity per week for the previous year and if they had a peak oxygen consumption (VO2 peak) between 15 and 35 ml/kg/min as determined by a continual progressive leg cycle ergometer stress test. The women were admitted into the study if they met the following criteria: 1) were diet and weight stable for ≥ 6 months 2) did not have osteoporosis 3) had not taken estrogen ≥6 months or blood thinners such as aspirin ≥ 3 months before the study 4) had not had a hysterectomy 5) had normal lung function (forced expiratory volume in 1s of 70% or more) and 6) were disease and injury free as determined by a health history questionnaire and physical examination. Subjects were excluded if they had the metabolic syndrome, which is defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP/ ATP III) (24). The study protocol was approved by the University of California Committee for the Protection of Human Subjects (CPHS 2005-10-29) and subjects provided written informed consent.
Subjects underwent a total of three tests over the course of the study: one pre-training test and two post-training tests. The testing consisted of a 90-minute rest period followed by 60 minutes of continuous pedaling on a cycle ergometer. The first test was performed at 65% of pre-training VO2peak (PRE). This task was selected as it is consistent in duration with Institute of Medicine (IOM) physical activity recommendations (3), and because from practical experience it was the most strenuous prolonged exercise task that sedentary participants were capable of performing. One of the post-training tests was performed at the same absolute workload (65% of pretraining VO2peak) while the other post-training test was performed at the same relative workload (65% of new VO2peak). The two post-training tests were performed 2 weeks apart at weeks 10 and 12 respectively of the training period. The order of the two post-training tests was randomized and training continued between the two tests.
Body composition was measured by using a DEXA whole-body scanner (LUNAR, GE Medical Systems). Waist circumference was determined at the smallest circumference between the xiphoid process and the anterior iliac crest, while the hip circumference was measured as the largest circumference around the buttocks.
A 12- hour fasting blood sample was taken from each of the prospective subjects to obtain measurements for a basic metabolic panel, FSH, triglycerides (TG), high-density lipoprotein (HDL), and total cholesterol. FSH levels were used to confirm postmenopausal status, while levels of TG and HDL were used in conjunction with other parameters to assess whether the subjects had metabolic syndrome.
Three-day diet records (two weekdays and 1 weekend day) were recorded and analyzed before and after the 12-week endurance-training program to monitor each subject’s caloric intake and macronutrient composition and to ensure that the subjects had maintained the same dietary habits throughout the course of the study. Analysis of dietary records was performed using the Nutritionist III program (N-squared Computing, Salem, OR). Subjects were instructed not to alter their dietary habits or discretionary physical activity level over the course of the study. Subjects were weighed before every training session and test and told to increase their energy intake to compensate for the increase in energy expenditure to maintain weight stability.
VO2peak tests were conducted under medical supervision as per ACSM guidelines. VO2peak was determined by a progressive test on an electronically braked cycle ergometer (Monark Ergometric 839E, Vansbro, Sweden) with a power output that began at 50 Watts and was increased by 25 Watts every 3 minutes until volitional exhaustion. Respiratory gases were continuously monitored throughout the test using an open-circuit on-line automated gas-analysis system (ParvoMedics TrueMax 2400, Salt Lake City, UT) system that was calibrated prior to the test using room air and a certified calibration gas. Heart rate was monitored continuously using a Quinton 759 electrocardiogram (Seattle, WA) and blood pressure was measured by auscultation. Subjects were considered to have reached their VO2peak when the following criteria were met: 1) leveling off of oxygen consumption (VO2) with increasing workload 2) an RER value greater than 1.1 and 3) a heart rate within 10% of their age-predicted maximum.
Subjects were instructed not to exercise on the day before testing and to only eat the standardized diet that was provided to them (2051 ± 58 kcal: 24% fat, 58% carbohydrate, and 18% protein). This standardized diet was based on IOM predictive equations for total energy expenditure (TEE) assuming a physical activity coefficient of 1.14, or physical activity level of 1.5, low active (3, 19). The physical activity coefficient is used in the prediction equations for total energy expenditure, while the physical activity level represents a measure of TEE in relation to basal energy expenditure (BEE) (PAL=TEE/BEE) (3). Subjects were instructed not to drink caffeine-containing beverages 24 hours prior to testing. Subjects reported to the laboratory 9-hour fasted on the morning of the test and catheters were then placed into the hand or wrist vein to obtain an “arterialized” blood samples using the “heated hand vein” technique for measurements of fasting blood glucose (18).
After collection of the background blood and breath measurements, subjects were given a standardized breakfast (560 kcal; 60% carbohydrate, 26% fat, and 14% protein) to consume in the laboratory that consisted of a whole-wheat bagel, peanut butter, and orange juice. Due to a work conflict, one subject completed her testing in the afternoon, arriving at the laboratory at noon to begin each test. However, this subject consumed the same standardized pre-test meal as the other subjects. A different standardized breakfast (565 kcal; 61% carbohydrate, 27% fat, 12% protein) was provided to this subject to eat on the morning of the test. We choose to study subjects under post-prandial conditions to mimic the normal free-living conditions and report data on postmenopausal women with stable exercise blood glucose levels and normal pre-exercise liver glycogen stores.
Respiratory gas exchange measurements and blood samples were collected during the test at 0, 60, 75, and 90 minutes of rest and during 15, 30, 45 and 60 minutes of exercise. Heart rates and blood pressures were recorded throughout rest and exercise at the same frequency as the blood and breath sampling.
After background sampling, blood samples were taken at 60, 75, and 90 minutes of rest and at 15, 30, 45 and 60 minutes of exercise. Blood samples for analysis of glucose and lactate were immediately deproteinized with 8% perchloric acid, mixed thoroughly, and then stored on ice before centrifugation at 3000g for 10 minutes. Perchloric acid extracts for glucose and lactate analyses were stored at -20°C until further analysis. All samples from a given subject were analyzed at the same time in duplicate to reduce variability.
Hematocrit was measured at each of the time-points using a circular microcapillary tube reader (No. 2201, International) and verified to be stable so as not to compromise the metabolite and hormone concentration measurements due to plasma shifts. Subjects drank tap water ad libitum during each test to maintain hydration status.
Standard equations were used to estimate the energy derived from carbohydrate and lipid oxidation (12).
where: RER is respiratory exchange ratio, VO2 is oxygen consumption expressed in liters per minute, and NPRQ is the non-protein RQ that was derived from the RER. The rate of carbohydrate oxidation, lipid oxidation, and energy expenditure were calculated using the nonprotein RQ values for each time point. We made the assumption that the percent contribution of protein to the resting metabolic rate was equivalent to the percentage of protein in the standardized diet and that the rate of protein oxidation would not be altered in the transition from rest to exercise.
The training intervention involved 60 minutes of supervised moderate-intensity exercise 5 days/wk for 12 weeks. The exercise consisted of pedaling on a cycle ergometer 4 days/wk and walking on a treadmill for 1 day/wk. The heart rate data from the VO2peak tests was used to estimate the target training heart rates needed to elicit 50 and 65% VO2peak. Duration and intensity of the exercise training was gradually increased. During the first three weeks of training, the exercise intensity was gradually increased from 50 to 65% VO2peak. The duration of the exercise training sessions was gradually increased from 30 to 60 minutes during the first four weeks. The number of supervised training sessions was increased gradually from 3 days per week during the first three weeks to five days per week during weeks 5-12. By week 5, subjects were exercising for 60 min at 65% VO2 peak 5 days/week; this intensity and duration was continued throughout the course of the intervention. Interval training was added during the last four weeks such that during training sessions subjects performed 4 one-minute bouts at a power output that elicited 100% VO2peak. Training took place at the study facility and was supervised by student personal trainers who were UC Berkeley students that had completed coursework in exercise physiology and were Red Cross CPR certified. Trainers used Polar heart rate monitors and data from the intermediate (5-week) VO2peak test to monitor and standardize the relative exercise intensity in training. Subjects were weighed before each training session and asked to increase their energy intake to maintain the same body weight. All subjects complied with the exercise training protocol and remained in the study for the entire duration.
Data are presented as group means ± SE. For evaluation of significance of responses to exercise and training blood metabolite concentration values for the last 15 minutes of rest (75 and 90 min) and the last 30 minutes of exercise (30, 45, and 60 min) were averaged to give representative values. Significance of differences among the metabolite concentrations and substrate oxidation rates were determined using one-way ANOVA with repeated measures while glucose and lactate measurements over time were analyzed using a two-way ANOVA with repeated measures. Significance of differences among the mean values in physical characteristics of the subjects were analyzed with paired student t-tests. Post hoc comparisons were made with Fischer’s protected least significant difference test. Statistical significance was defined as an alpha ≤ 0.05.
Physical characteristics and work capacities of the subjects before and after training are listed in Tables 1 and and2.2. Subjects were weight stable throughout the intervention. Measurement of body composition as determined by DEXA indicated that training did not alter body composition.
The ergometric and physiological parameters of subjects during rest and exercise before and after training are listed in Table 3. Maximal workload achieved during VO2 max testing increased by 25.3 ± 3.4% and VO2peak increased by 16.3 ± 3.9% as a result of training (p < 0.05, Table 1). Because of the training effect, the post-training test at the same absolute exercise intensity was equivalent to 55% of the post-training VO2peak. Resting heart rate values were lower after training and pulmonary minute ventilation, heart rate, diastolic blood pressure and mean arterial pressure were all reduced during exercise at the same absolute (p < 0.05), but not relative exercise intensity (Table 3).
There were no changes in the total energy intake (1845 ± 124 and 1823 ± 98 kcal/day), percentage of energy intake as carbohydrate (48 ± 2.7 and 49 ± 2.7%), percentage of energy intake as fat (40 ± 2.2 and 42 ± 3.7%) and percentage of energy intake as protein (18 ± 1.1 and 18 ± 1.0% before and after training, respectively) as a result of the exercise intervention.
There was no significant difference between the resting plasma glucose concentrations before and after training (Table 4). Before training blood glucose concentrations decreased 22% from rest to exercise (p < 0.05). After training, the decrease in blood glucose concentration from rest to exercise was 16% during the same absolute exercise intensity and 30% during the same relative exercise intensity (Table 4). Blood glucose concentrations during the same relative exercise intensity were 16% lower than pretraining and 17% lower during the same absolute intensity (p < 0.05).
Training induced such a profound change in blood lactate concentration during exercise that lactate did not rise significantly over rest during the same absolute exercise intensity and was reduced by 45% during the same relative exercise intensity albeit a 35% increase in exercise power output (p < 0.05, Table 4). The lactate concentration during exercise before training was higher than both post-training exercise tests at every exercise time point (p < 0.05, Figure 1).
RER values increased in the transition from rest to exercise before training but not after training (p < 0.05, Table 4). Compared to pretraining, after training RER was lower indicating a decreased reliance on carbohydrate (Fig 2A) and an increased reliance on lipid (Figure 2B) during exercise at the same absolute, but not relative intensity. Correspondingly, the energy from carbohydrate decreased and the energy from lipid increased during the same absolute exercise intensity compared to pretraining. Exercise energy expenditure during the same relative intensity after training was 16.7% greater than during the same absolute intensity (p < 0.05), but there was no significant difference between pretraining and absolute intensity (Table 4).
In previous studies on young women treated similarly as were the postmenopausal women enrolled in the current investigation, endurance training increased cardiorespiratory capacity and decreased total carbohydrate oxidation at the same absolute and relative exercise intensities (14). Now we report that 12 weeks of supervised endurance training induced classic physiological adaptations (i.e. increased VO2peak, decreased resting heart rate, and decreased exercise heart rate during the same absolute but not relative exercise intensity) in postmenopausal women. In addition, endurance training resulted in decreased carbohydrate and increased lipid oxidation rates at the same absolute, but not relative exercise intensity. The physiological and metabolic adaptations seen in our study can be attributed to the effects of endurance training alone because our subjects remained diet and weight stable throughout the intervention.
Previous studies that have been conducted on postmenopausal women have been varied with regard to maintenance of dietary composition and weight stability. For example, Irwin et al. (20) found that postmenopausal women that underwent an exercise training intervention had significant changes in body weight, total body fat, and intra-abdominal fat compared to unexercised controls. To induce weight loss in some studies investigators purposely altered subject diets via caloric restriction (6), while in other studies investigators employed a combination of exercise training and caloric restriction to decrease the subjects’ body weight (6, 20).
Because caloric restriction and weight loss can independently affect metabolism, we successfully isolated the effects of endurance training on parameters of metabolic and cardiovascular fitness. Nonetheless, with limitations our data can be contrasted with those obtained in studies using a mixed gender study design including older women (29). Given the variability in the extant literature on training effects on older men and postmenopausal women, we sought to control diet and body weight and study women within the first years following menopause.
The 16% increase in VO2 peak seen in our study is consistent with previously observed aerobic training effects on postmenopausal women (15, 25). While physiologically significant, the 16% increase in VO2peak is less than the 25% increase found in younger premenopausal women who underwent a similar training protocol (14), indicating that the cardiovascular training response is dampened in women after menopause. One of the contributing factors may be an inability of postmenopausal women to increase their peak cardiac output and stroke volume (33). Spina et al. found that while exercise training increased peak stroke volume and improved left ventricular systolic function in young women after 9-12 months of endurance training, (31), these same improvements were not seen in the older women (60-70 yr) despite their significant improvements in cardiovascular fitness (33). Similarly, O’Donnell et al. reported that 12 weeks of endurance training in postmenopausal women increased VO2peak but did not result in changes in stroke volume, cardiac output, or total peripheral resistance (25). Estrogen deficiency may partly account for the blunted cardiovascular response in postmenopausal women (33) because previous studies on healthy postmenopausal women have found significant improvements in left ventricular ejection fraction, stroke volume, and cardiac output after hormone replacement therapy (30). Together, these findings may help to explain why the cardiovascular adaptations to endurance training in postmenopausal women were dampened relative to premenopausal women.
The significant 4 bpm decrease in resting heart rate after training may be attributed to a decrease in the intrinsic heart rate or an increase in vagal tone. The 19 bpm decrease in heart rate at the same absolute exercise intensity is less than the 27 bpm decrease seen in young premenopausal women (14), providing further evidence for the dampened cardiopulmonary training response in postmenopausal women. However, despite the dampened training response, the postmenopausal women in the present study still demonstrated significant improvements in cardiovascular adaptations such as a 7 mmHg decrease in the diastolic pressure and a 8 mmHg decrease in mean arterial pressure at the same absolute workload. Together these findings indicate that healthy normotensive postmenopausal women have the ability to induce significant improvements in cardiovascular parameters after endurance training.
The 12-week training intervention resulted in many of the classic metabolic adaptations as seen in previous studies. Specifically, after training the postmenopausal women had a decrease in lactate concentration at the same absolute and relative exercise intensities, a decrease in RER and an increased reliance on lipid as an energy source during the same absolute exercise intensity.
The decrease in carbohydrate oxidation during submaximal exercise after endurance training may be partly attributed to a slower rate of glycogenolysis and an increased capacity of muscle to oxidize lipid in postmenopausal women. Endurance training increases the mitochondrial content and the sensitivity of respiratory control such that a given exercise can be accomplished at a higher ATP/ADP ratio leading to a decrease in the glycolytic flux and the rate of muscle glycogenolysis (17). Molé et al. showed that after rats underwent a treadmill training program they had an increase in the enzymatic capacity of muscle to oxidize lipid as shown by increased amounts of carnitine palmitoyl transferase, palmitoyl CoA dehydrogenase, and mitochondrial ATP-dependent palmitoyl CoA-synthetase (23). These peripheral adaptations seen with endurance training increase the capacity for ATP production and help to promote the increase in lipid utilization during submaximal exercise after endurance training.
In addition to peripheral adaptations, a decrease in the sympathetic system activation after endurance training may have also contributed to alterations in substrate partitioning in our study population. Previous studies have demonstrated that the sympathetic system activation is proportional to the relative exercise intensity and the magnitude of this hormonal response declines with training (8). Therefore, in contrast to previous endurance studies on postmenopausal women that have only taken post-training measurements at the same absolute exercise intensity (25, 29), our measurements of relative exercise intensity allow us to compare the pre- and post-training conditions in the context of a relatively similar hormonal environment (36). Obtaining measurements at the same relative exercise intensity gives a standard by which investigators are able to compare results from studies involving different age groups and fitness levels. Our finding of a decrease in carbohydrate oxidation at the same absolute, but not relative exercise intensity indicates that both hormonal and peripheral training adaptations may account for the training induced alterations in postmenopausal women.
Our finding of a decrease in RER at the same absolute exercise intensity after endurance training is similar to studies in younger men (1) and older individuals (29). However, our findings differ from the results of Friedlander et al. (14) who found that an endurance-training program resulted in a significant reduction in RER at the same absolute and relative exercise intensities in young women. Furthermore, the training response at the same absolute exercise intensity was dampened in postmenopausal women because young women had a 22% average decline in total carbohydrate oxidation versus an 11.5% average decline seen in postmenopausal women (14). These findings indicate while postmenopausal women respond to training, the magnitude of training-induced adaptations in energy-substrate partitioning are less than those in similarly treated young women.
Since estrogen has been shown to have significant effects on carbohydrate and lipid metabolism, the lower levels of estrogen at menopause may partly account for the dampened metabolic training response in postmenopausal women compared to younger women. Specifically, estrogen has been shown to have an effect of decreasing carbohydrate oxidation by decreasing muscle glycogenolysis in humans (4, 7). Studies in rats have demonstrated that estrogen can increase FFA availability to the muscle during exercise (10) and shift the substrate partitioning toward lipid (16). Because of the known lipolytic effects of estrogen, the withdrawal of estrogen at menopause may make postmenopausal women more resistant to training-induced alterations in substrate partitioning in comparison to premenopausal women and may partly explain the smaller decline in total carbohydrate oxidation at the same absolute exercise intensity after training and lack of a training effect on substrate partitioning at the same relative exercise intensity.
Our finding that resting metabolic rate did not change after training is similar to other studies on postmenopausal women (27). Since lean body mass has been shown to have an association with resting metabolic rate (21), we may not have seen a change in resting metabolic rate because there was not a significant change in fat free mass (Table 1). Furthermore, unlike results from other studies (5, 14) we did not see a significant increase in fat oxidation at rest after training. Friedlander et al. (14) reported an increase in resting fat oxidation in young women after training. Our finding of an unchanged resting RER is similar to that seen in young men who underwent a similar endurance-training program as ours (14). Thus, the decrease in estrogen at menopause may partly account for this finding, as our results tend to parallel those seen in younger men rather than younger women. The unaltered resting metabolic rate or change in resting RER after endurance training further underscores that postmenopausal women may be resistant to some of the beneficial effects of endurance training that are commonly seen in premenopausal women.
The resting RER and substrate oxidation data that we report are on 3-hour postprandial postmenopausal women, while other studies on postmenopausal women and elderly subjects have reported values on overnight fasted individuals (28, 29). One notable difference was that the resting RER values of our subjects were significantly higher than those seen in other studies in which younger men and women underwent a similar training and testing protocol (0.93 vs. 0.84-younger women or 0.86-younger men) (13, 14). The higher resting RER may be attributed to several age-related factors including subclinical gastroparesis and developing insulin resistance (34). Menopause is associated with an increase in fasting insulin levels (31) and increased incidence of impaired glucose tolerance (34). Concern is that this pattern of increased carbohydrate oxidation and diversion of lipid to storage could contribute to the increase in central adiposity (35) and weight gain (37) that is commonly seen after menopause.
While the sample size of our study was small and the exercise intervention was short, we report similar increases in cardiovascular fitness as seen in other studies with more subjects (15, 25). In addition, the exercise-training program in our study was physically demanding and women recruited for the study were healthy and had to be in reasonable physical condition, thereby excluding a certain subset of postmenopausal women. We excluded women with the metabolic syndrome because the purpose of our study was to investigate the effects of endurance training on healthy postmenopausal women without metabolic abnormalities or on medications. Some of the strengths of our study include the following: 1) subjects remained diet and weight stable throughout the intervention 2) all exercise training sessions were supervised and 3) all subjects complied with the study protocol and completed the study.
In summary, the main finding of this study was that 12 weeks of supervised endurance training in healthy postmenopausal women improved cardiorespiratory fitness, decreased blood lactate concentrations during exercise at the same absolute and relative exercise intensities, and increased reliance on lipid and decreased reliance on carbohydrate at the same absolute intensity after training. The results of this study indicate that despite the changes in the hormonal milieu and metabolic changes that occur at menopause, postmenopausal women have directionally similar, though blunted training adaptations as that seen in younger women.
Supported by NIH grant R01 AR042906 to GAB. The authors thank the subjects for their participation and compliance with training and experimental procedures and good cheer. They are truly amazing and accomplished people. T. Mau, P. Nguyen, T. Nguyen, M. Patella, E. Mayeda, B. Martinelli, and N. Wortham are thanked for their technical support and assistance. C. Chang, S. Dixit, A. Luke, and H. Masket are thanked for providing medical coverage during exercise stress testing.
The study protocol was approved by the University of California Committee for the Protection of Human Subjects (CPHS 2005-10-29) and subjects provided written informed consent.
There is no conflict of interest with regard to this research.
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