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Am J Physiol Heart Circ Physiol 295: H842-H850, 2008. First published June 20, 2008; doi:10.1152/ajpheart.91426.2007
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Exercise training impacts the myocardial metabolism of older individuals in a gender-specific manner

Pablo F. Soto,1,3 Pilar Herrero,3 Kenneth B. Schechtman,4 Alan D. Waggoner,1 Jeffrey M. Baumstark,3 Ali A. Ehsani,1,2 and Robert J. Gropler1,3

1Cardiovascular Division and 2Division of Geriatrics and Nutritional Sciences, Department of Medicine, 3Department of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, and 4Department of Biostatistics, Washington University School of Medicine, St. Louis, Missouri

Submitted 12 December 2007 ; accepted in final form 16 June 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Aging is associated with decreases in aerobic capacity, cardiac function, and insulin sensitivity as well as alterations in myocardial substrate metabolism. Endurance exercise training (EET) improves cardiac function in a gender-specific manner, and EET has been shown to improve whole body glucose tolerance, but its effects on myocardial metabolism are unclear. Accordingly, we studied the effect of EET on myocardial substrate metabolism in older men and women. Twelve healthy older individuals (age: 60–75 yr; 6 men and 6 women) underwent PET with [15O]water, [11C]acetate, [11C]glucose, and [11C]palmitate for the assessment of myocardial blood flow (MBF), myocardial O2 consumption (MVO2), myocardial glucose utilization (MGU), and myocardial fatty acid utilization (MFAU), respectively, at rest and during dobutamine infusion (10 µg·kg–1·min–1). Measurements were repeated after 11 mo of EET. Maximal O2 uptake (VO2max) increased (P = 0.005) after EET. MBF was unaffected by training, as was resting MVO2; however, posttraining dobutamine MVO2 was significantly higher (P = 0.05), as was MGU (P < 0.04). Although overall dobutamine MFAU was unchanged, posttraining dobutamine MFAU increased in women (P = 0.01) but decreased in men (P = 0.03). Thus, EET in older individuals improves the catecholamine response of myocardial glucose metabolism. Moreover, gender differences exist in the myocardial fatty acid metabolic response to training. These findings suggest a role for altered myocardial substrate metabolism in modulating the cardiovascular benefits of EET in older individuals.

aging; catecholamine; fatty acid; glucose; insulin resistance

AGING is associated with decreased aerobic capacity manifest as a 10% per decade decline in maximal O2 uptake (VO2max) in sedentary individuals after the age of 25 yr (46). Endurance exercise training (EET) in older individuals can partially restore this age-mediated decline in VO2max by favorable improvements in left ventricular (LV) function, myocardial blood flow distribution, and skeletal muscle oxidative capacity and function (19). Recent evidence suggests that gender plays a significant role in these physiological adaptations; older women adapt mostly by increasing arteriovenous O2 differences, whereas in older men a large portion of the training-induced gain in VO2max is attributable to higher cardiac output and stroke volume during maximal exercise (14, 45, 46). Although physiological LV hypertrophy (LVH) and an enhanced response to catecholamines have been implicated, the mechanisms responsible for increases in cardiac function in response to EET have been incompletely defined (47).

An increasing body of evidence suggests that cardiac metabolism may play an important role in mediating these functional changes. Fatty acid metabolism is downregulated in both the aging heart and LVH, with an increased reliance on cardiac glucose metabolism (11, 30). Moreover, aging is associated with an impaired ability for the heart to increase glucose metabolism in response to catecholamine stress (44). Aging is also associated with a decline in whole body insulin sensitivity, primarily related to increased abdominal adiposity (31). Although exercise training has been shown to have beneficial effects on whole body glucose tolerance and insulin action (29), even among older individuals (16), the effect of exercise training on myocardial metabolism has not been previously described. We hypothesized that EET improves myocardial glucose and fatty acid metabolism in a gender-specific manner.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
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Study population. The study population consisted of 12 healthy, nonobese, older, sedentary individuals (6 men and 6 women) of 60–75 yr in age recruited specifically for this study. All volunteers completed a comprehensive screening medical evaluation, including a medical history, physical examination, electrocardiogram, complete lipid profile, and exercise stress echocardiography for the detection of cardiac abnormalities. Exclusion criteria included an abnormal rest or exercise echocardiogram, elevated fasting glucose (>100 mg/dl), impaired glucose tolerance, diabetes, hypertension, a history of coronary artery or other cardiac disease, a history of smoking within the last 12 mo, or routine aerobic exercise of ≥30 min/day for >2 days/wk. Baseline (pretraining) data from these individuals have been previously published (21, 30, 44). Written informed consent was obtained from all volunteers before participation in this study, which complied with the Declaration of Helsinki and was approved by the Institutional Review Board and General Clinical Research Center of Washington University School of Medicine.

Experimental procedures and cardiac PET imaging. All volunteers fasted overnight for at least 12 h before each PET scan. All PET scans were performed starting at 8:00 AM to avoid circadian variations in myocardial metabolism and function (54). Quantification of myocardial blood flow (MBF), myocardial O2 consumption (MVO2), myocardial glucose extraction fraction (MGEF), and myocardial glucose utilization (MGU) as well as myocardial fatty acid extraction fraction (MFAEF), myocardial fatty acid utilization (MFAU), the oxidative component of myocardial fatty acid metabolism (MFAO), and %MFAO were obtained by PET and [15O]water (up to 28 mCi), [1-11C]acetate (up to 21 mCi), [1-11C]glucose (up to 21 mCi), and [1-11C]palmitate (up to 21 mCi), respectively, using well-validated techniques, as previously reported (3–5, 22). Fractional myocardial glucose uptake (MGUp) and fatty acid uptake (MFAUp) (both in ml·g–1·min–1) represent the fraction of glucose and free fatty acids (FFA), respectively, extracted by the heart after correction for changes in MBF; these parameters quantify the intrinsic ability of the heart to extract substrate and were calculated as follows:

Formula 1(1)

Formula 2(2)
where MGU and MFAU (both in nmol·g–1·min–1) represent the total utilization of extracted glucose and FFA, respectively, taking into account substrate levels in the peripheral circulation. %MFAO represents the fraction of extracted fatty acid oxidized and was calculated as %MFAO = MFAO/MFAU x 100.

To determine the metabolic response to low-level catecholamine stress, volunteers returned for repeat cardiac PET imaging on a separate day. At that time, an identical imaging protocol was performed during continuous intravenous infusion of low-dose dobutamine (10 µg·kg–1·min–1) begun 15 min before each PET scan. These procedures were well tolerated by all participants.

Training program. Participants first completed ~8 wk of daily stretching and flexibility exercises to prepare them for the EET program. After completion of the flexibility exercises, they underwent baseline Formula 2O2max testing with a previously described protocol (15). The EET program consisted of walking, running, or cycling exercises 4–5 days/wk for ~1 h/session for 11 mo. Exercise intensity was measured with radio telemetry. The initial intensity of the exercise was adjusted to require 60–70% of the participant's Formula 2O2max for the first 3 mo. Thereafter, intensity was increased progressively to 70–80% of Formula 2O2max supplemented by additional brief intervals of intense exercise requiring 90–100% of Formula 2O2max two or three times per week. Formula 2O2max was measured at 3-mo intervals to maintain training intensity relative to the current Formula 2O2max. After completion of the training regimen, volunteers returned for repeat rest and dobutamine PET imaging for the determination of MBF, MFormula 2O2, and myocardial glucose and fatty acid metabolism. In one female volunteer, posttraining dobutamine PET imaging for the assessment of fatty acid metabolism was unable to be performed due to technical reasons.

Echocardiography. All volunteers underwent two-dimensional and Doppler echocardiographic examination with a Sequoia-C256 (Acuson-Siemens, Mountain View, CA) under resting conditions both before and after EET. The echocardiographic experiments and analysis were performed by a single observer (A. D. Waggoner) in all cases. LV ejection fraction was calculated from end-diastolic and end-systolic volumes determined by the modified Simpson's method. LV mass was determined by the area-length method and indexed to body surface area to calculate the LV mass index, according to the recommendations of American Society of Echocardiography (41).

Plasma substrate and insulin analyses. Plasma glucose concentrations (in mg/dl) were determined by the Cobas Mira analyzer (Roche Diagnostics, Indianapolis, IN). FFA concentrations were measured by an enzymatic colorimetric method (NEFA C kit, WAKO Chemicals, Richmond, VA). Lactate was measured with a photospectrometry kit (Sigma Chemicals, St. Louis, MO). Insulin was measured by radioimmunoassay (Linco Research, St. Charles, MO).

Statistical analysis. Statistical calculations were performed by SAS version 8.2. Data are means ± SD. Gender differences in baseline parameters were evaluated by unpaired t-tests. Treatment effects of dobutamine and exercise training were determined by two-way ANOVA with repeated measurements. Gender differences in the dobutamine effect and the training effect on myocardial fatty acid metabolism parameters were determined separately by two-way ANOVA. A P value of <0.05 was considered statistically significant.


   RESULTS
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 RESULTS
DISCUSSION
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Baseline characteristics. Baseline characteristics of the subjects (6 men and 6 women) are shown in Table 1. No differences were found between men and women regarding age, total cholesterol, LDL, or triglyceride levels. Baseline Formula 2O2max values were within 1 SD of expected values for sedentary individuals of comparable age and gender (25). The mean body mass index (BMI) was lower and mean HDL level was higher in women. Volunteers exercised an average of 3.1 days/wk (range: 2.1–4.0 days/wk) for 44 wk (range: 42–44 wk) at 78% of the maximal heart rate (range: 59–94%).


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  		Table 1. Baseline parameters

 
Impact of EET on hemodynamics, Formula 2O2max, BMI, adiposity, LV structure and function, MBF, and MFormula 2O2. The effects of training and dobutamine infusion are shown in Table 2. As expected, systolic blood pressure, heart rate, and the rate-pressure product increased and diastolic blood pressure decreased with dobutamine infusion. Hemodynamic parameters, both at baseline and during dobutamine infusion, were unchanged with EET. Formula 2O2max increased after training, as did Formula 2O2max normalized to body weight. BMI did not change with EET. Absolute LV mass, LV mass index, and LV ejection fraction were unchanged after training. Of note, there were no gender-specific differences in the response to EET for any of these paramenters (data not shown).


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  		Table 2. Effect of exercise training on hemodynamics, aerobic capacity, cardiac structure/function, MFormula 3O2, and MBF

 
As shown in Table 2, MFormula 2O2 increased in response to dobutamine both before and after training. Compared with pretraining values, resting MFormula 2O2 was unchanged, but dobutamine MFormula 2O2 increased by 19%, indicating a training effect. MBF also increased with dobutamine administration both before and after training, but neither rest nor dobutamine values were affected by exercise training. MBF was consistently higher in women, but no gender differences were found in the effect of training or dobutamine on MBF (Table 3) or MFormula 2O2 (data not shown).


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  		Table 3. Gender-specific effects of exercise training on myocardial fatty acid metabolism

 
Effects of EET on plasma substrate levels and insulin. Figure 1 shows plasma substrate and insulin levels. Glucose levels were minimally lowered with dobutamine before training, and no dobutamine effect was seen after training; furthermore, no training effect was detectible. Both FFA and insulin levels increased with dobutamine before and after training with no training effect observed. Before training, lactate levels were unaffected by dobutamine but then trended lower with dobutamine after training (Fig. 1). No gender differences were found in the effect of training or dobutamine on glucose, lactate, or insulin levels (data not shown).


Figure 1
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  		Fig. 1. Plasma free fatty acid, glucose, lactate, and insulin levels during PET imaging at rest and during intravenous dobutamine infusion both before (Pre) and after (Post) endurance exercise training (EET). Values are means ± SD. *P ≤ 0.01 vs. rest; {dagger}P = 0.05 vs. rest; {ddagger}P = 0.08 vs. rest.

 
Effect of EET on myocardial glucose metabolism. Before training, rest and dobutamine MGUp were similar (Fig. 2). Compared with pretraining values, posttraining rest MGUp was unchanged, but dobutamine MGUp was increased (P = 0.03). Similarly, dobutamine did not induce any significant change in MGU either before or after training; compared with pretraining values, posttraining rest MGU was unchanged, but dobutamine MGU was increased (P = 0.04). No gender differences were found in the effect of training or dobutamine on myocardial glucose metabolism (data not shown).


Figure 2
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  		Fig. 2. Effect of EET on myocardial glucose metabolism at rest and during intravenous dobutamine infusion both pre- and post-EET. MGUp, fractional myocardial glucose uptake; MGU, myocardial glucose utilization. Values are means ± SD. *P = 0.03 vs. Pre; {dagger}P = 0.04 vs. Pre.

 
Effect of EET on myocardial fatty acid metabolism. Dobutamine induced no changes in fatty acid uptake compared with rest conditions either before or after training (Fig. 3). However, because of the catecholamine-induced increase in serum FFA levels, MFAU increased. This increase was similar before and after EET. MFAO demonstrated a similar pattern of response to dobutamine, both before and after training. Before training, %MFAO remained unchanged with dobutamine. After EET, dobutamine induced a decline in %MFAO. Moreover, dobutamine %MFAO posttraining was lower compared with pretraining values, suggesting a training effect toward reduced percentage of fatty acid oxidation with dobutamine.


Figure 3
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  		Fig. 3. Effect of EET on myocardial fatty acid metabolism at rest and during intravenous dobutamine infusion both pre- and post-EET. MFAU, myocardial fatty acid utilization; MFAO, myocardial fatty acid oxidation; %MFAO, percentage of fatty acid uptake that is immediately oxidized. Values are means ± SD. *P < 0.01 vs. rest; {dagger}P = 0.05 vs. rest; {ddagger}P = 0.05 vs. Pre.

 
Effects of gender on myocardial fatty acid metabolism. Table 3 shows gender-specific data for parameters of myocardial fatty acid metabolism as well as gender differences by two-way ANOVA in both the response to dobutamine and to EET. Before training, men exhibited a more pronounced MFAU and MFAO response to dobutamine primarily as a result of an augmented response of serum FFA levels. A gender difference in the dobutamine response also was seen after training; however, it was the reverse of what was seen at baseline. Men now had a diminished MFAU and MFAO response to dobutamine, primarily due to a diminished response in FFA levels. For the most part, no gender differences were found in the training effect on resting values of fatty acid metabolism, although a trend toward a differential EET response of resting fatty acid uptake was seen; absolute values of fatty acid uptake increased in men and decreased in women (gender difference in training effect: P = 0.06; Table 3). Interestingly, although no gender differences were seen in the training effect of resting FFA levels, a posttraining gender difference developed (P = 0.05) that mirror gender differences in posttraining MFAU and MFAO (P < 0.01 for both; Table 3). Finally, a gender difference in the training effect on dobutamine MFAU and MFAO was seen that was not evident in the pooled data shown in Fig. 3; training induced an overall decline in these parameters in men, whereas they were increased in women. These changes corresponded to changes in FFA levels.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We evaluated the effect of EET on myocardial substrate metabolism in healthy, older individuals. The results demonstrate that after 11 mo of EET, Formula 2O2max increased 17% in tandem with 1) a 19% increase in MFormula 2O2 and 2) a 50% increase in overall MGU at a fixed dose of dobutamine. These increases were not driven by changes in serum glucose or insulin levels, suggesting a training-induced increase in intrinsic MGUp. Moreover, a gender difference was detected in the cardiac metabolic response to exercise training. In women, MFAU and MFAO levels during dobutamine were augmented by training, whereas in men dobutamine MFAU and MFAO declined after EET. These differences in myocardial fatty acid metabolism reflect primarily differential responses in plasma fatty acid levels to dobutamine before and after exercise training. Gender differences were not seen in the myocardial glucose metabolism response to training.

Myocardial glucose metabolism. The aging heart experiences a decline in MFAU and MFAO with an increase in the relative contribution of MGU (30). In addition, older individuals are not able to increase MGU in response to catecholamine stress (44). In the present investigation, post-EET rates of dobutamine MGU increased. Moreover, they approached levels seen in younger individuals, both in terms of absolute value (221 ± 104 vs. 209 ± 78 nmol·g–1·min–1) and response to dobutamine (+50 vs. +60 nmol·g–1·min–1) (44). These results suggest that exercise in older individuals may reverse some of the age-related changes in cardiac metabolism.

With aging comes a decline in the insulin sensitivity of skeletal muscle that improves with exercise training (13, 26). One mechanism that mediates this effect is an increase in the concentration of insulin-sensitive glucose transporter 4 (GLUT4) (7). Exercise training in patients with dilated cardiomyopathy has been shown to improve insulin-stimulated MGUp, as measured with [18F]fluorodeoxyglucose (50). Although quantitative measures of whole body insulin sensitivity were not part of the present study, the lack of change in glucose and insulin levels with training, in the setting of a higher dobutamine MGU, is consistent with a training-induced improvement in myocardial insulin sensitivity. Indirect effects of improved insulin sensitivity also can be seen in the pattern of myocardial fatty acid metabolism. %MFAO is increased with the relative insulin resistance of Type 1 diabetes mellitus (20); in the present study, EET induced a decline in dobutamine %MFAO compared with pretraining values, suggesting an improved insulin effect. The lack of an increase in MGU at rest post-EET may simply reflect the difficulty in detecting differences in MGU when it is at a low level, such as occurs under the fasting conditions used in this study. However, this absence of a similar increase in rest MGU suggests that the impact of EET on metabolism may be primarily due to improved myocardial metabolic sensitivity to dobutamine stimulation.

Myocardial fatty acid metabolism: gender differences at rest. Before training, women showed a trend toward a higher resting MBF (P = 0.07), consistent with previously published findings (21). We have previously demonstrated that hormone replacement therapy containing solely estrogen in postmenopausal women increases MFAU and MFAO, most likely as a combined effect on both increasing serum FFA levels (peripheral effect) and myocardial fatty acid extraction (central effect) (21). However, the addition of progesterone counterbalanced this effect. Although half of the women in the present study were on hormone replacement therapy, baseline resting MFAU and MFAO were not significantly different compared with men.

Gender differences during dobutamine infusion. At baseline, male subjects increased FFA levels with inotropic stimulation to a greater extent than did women, resulting in higher MFAO and MFAU. Release of FFA from adipose tissue is regulated by the sympathetic nervous system, and numerous examples exist of gender differences in sympathetic nervous system activity (51). In young women, the catecholamine response to stress is lower compared with men, but women have a similar or greater rate of lipolysis, suggesting they may be more sensitive to the lipolytic action of catecholamines (24). Thus, with inotropic stimulation, women should have higher FFA levels than men, assuming similar rates of clearance. However, rest and exercise studies of whole-body metabolism in an older population have demonstrated no gender differences in plasma FFA levels either at rest or with exercise. Nevertheless, overall rates of fat oxidation are higher in older men at rest, although with exercise these gender differences disappear (51). Potential explanations for our observed gender dimorphism at baseline may include gender differences in rates of clearance or catecholamine sensitivity, some of which may manifest only with advanced age or with sedentary status.

Gender difference and exercise training. Evidence from experimental models has shown that exercise training improves the age-related decline in cardiac fatty acid metabolic capacity (10, 36, 39, 49). This mechanism is potentially an attenuation of the aging-induced decrease of mRNA and protein expression of peroxisome proliferator-actived receptor (PPAR)-{alpha} (27). However, these studies were primarily conducted in male animals. In humans, as little as 12–16 wk of EET increases fat oxidation from endogenous sources in skeletal muscle of older adults (37, 43). No gender differences were described in these investigations.

The mechanism responsible for the observed gender differences in the FFA response to dobutamine after training is unclear. Catecholamine-induced increases in FFA levels are mediated through stimulation of adipose tissue β-adrenergic receptors, resulting in lipolysis; thus, the observed gender dimorphism could be attributable to sex-specific changes in tissue sensitivity to β-adrenergic stimulation with training. In a cross-sectional study of adipocytes in younger individuals, endurance training led to better lipid mobilization, an effect that was greater in women than in men (8). The gender-specific FFA levels in the present study are consistent with this mechanism. Recent studies have indicated that both acute and chronic reductions in nitric oxide (NO) bioavailability can alter myocardial substrate consumption (9, 38); moreover, numerous age and gender effects on NO availability have been shown. In studies of vasomotor kinetics, advancing age produces a sex difference that is partially explained by a greater reduction in NO availability in males (1). Exercise training has been shown to increase plasma NO in humans (34). Moreover, adaptations of vascular reactivity in response to EET have been shown to greater in females than in males, though these results vary by anatomic location (33). A gender-specific improvement of cardiac NO availability in response to EET has yet to be demonstrated, but such a mechanism could explain the findings of the present study.

Gender differences in levels of certain adipokines have been observed both at rest and in response to exercise training. Adiponectin and leptin both increase skeletal muscle fatty acid oxidation by activating AMP-activated protein kinase (53). In a middle-aged insulin-resistant cohort, adiponectin has been shown to be higher in women, but no training effect was seen in either sex (35). Leptin has also been shown to be higher in sedentary women, and EET reduced these levels exclusively in women, but not down to levels observed in age-matched men (23). Neither of these mechanistic explanations alone would explain the present findings. IL-6 has also has been shown to mediate skeletal muscle metabolism. IL-6 levels are increased during bouts of acute exercise, increasing fatty acid oxidation by stimulating lipolysis and thus increasing lipid availability (2, 52). While no gender difference in this response has been observed, an observational study (18) in males has suggested that EET may attenuate this response. To our knowledge, gender differences in this training effect on the IL-6 response to exercise have not been investigated. Measurements of circulating adipokine levels were not part of the present study, but a gender-specific response of IL-6 levels to EET could explain the observed sex-specific response in FFA levels, MFAU, and MFAO. The potential role of adipokines, particularly IL-6, in the regulation of myocardial metabolism deserves further study.

Study limitations. Despite the increase in dobutamine MGU after training, estimates from stoichiometric calculations indicate that this increase did not account entirely for the increase in dobutamine MFormula 2O2 post-EET. The overall change in dobutamine MVO2 after EET was 1.8 µmol·g–1·min–1 (Table 2). Using stoichiometry, we can calculate the contribution of fatty acid metabolism to this overall change ({Delta}MFormula 2O2PAL) and estimate the remaining component ({Delta}MFormula 2O2nonPAL) from the following equation:

Formula 3(3)
As 23 molecules of O2 are consumed for each molecule of palmitate, a decline after training in dobutamine MFAO from 364 ± 137 to 314 ± 136 nmol·g–1·min–1 (Fig. 3) represents a change in MVO2 ({Delta}MFormula 3O2PAL) of –0.57 µmol·g–1·min–1, that is, the contribution from fatty acids to overall oxidation actually declined. The remaining O2 consumption ({Delta}MFormula 3O2nonPAL) is therefore +2.37 µmol·g–1·min–1, for which we need to account.

As we did not measure the oxidative component of MGU, it is unclear what percentage of MGU taken up is oxidized during dobutamine infusion. Even if we assume a 100% rate of oxidation, as 6 molecules of O2 are consumed for each glucose molecule, the contribution of MGU to {Delta}MFormula 3O2 is only 0.44 µmol·g–1·min–1, leaving unaccounted the majority of {Delta}MFormula 3O2nonPAL. The remaining increase in oxidative metabolism is unlikely to be derived from lactate, as posttraining dobutamine lactate levels were actually lower (Fig. 1). An increase in the recruitment of endogenous substrates such as glycogen has been shown in experimental animals after training (40), but it is unclear whether a similar physiological response is present in humans. As neither lactate metabolism, percent glucose oxidation, nor changes in glycogen and triglyceride metabolism were measured, the conclusions that can be drawn about the relative importance of EET-induced changes in MGU are limited.

Because of the technical limitations to performing cardiac PET during exercise, a continuous dobutamine infusion of 10 µg·kg–1·min–1 was used in the present investigation as a surrogate for the stress response of acute exercise; higher doses of dobutamine were not tolerated for the duration of a PET scan. On average, only 61% of the maximal predicted heart rate was achieved; thus, the present findings may represent submaximal exercise physiology. Because of the demanding nature of training protocol our sample size was limited, and neither young nor older untrained control groups were studied. We anticipate that our findings would be similar in a younger cohort, as clinical studies comparing responses to EET in younger and older cohorts have showm similar increases in Formula 3O2max, insulin action, and GLUT4 activity (7, 13, 32). EET-induced changes in insulin action can be mediated in part through changes in central adiposity (17); this parameter was not measured, although none of the volunteers was obese. As we did not measure percent body fat, it is possible that there was a gender-specific replacement of adipose tissue with fat-free mass, thus altering adipocyte biology in a sex-specific manner; however, findings from several investigations have suggested that body composition changes in older men and women are similar with EET (6, 42). Finally, our results may not be generalizable to older individuals who are obese, who exhibit significant dyslipidemia or insulin resistance, or who begin at a higher level of fitness, such as masters athletes.

Clinical implications. The observed reversal of the age-related changes in myocardial glucose metabolism suggests a mechanism and further underscores the health benefit of EET in older individuals. Moreover, because glucose is the substrate of choice during periods of ischemia (48), the present results suggest a mechanism by which training may increase the tolerance to myocardial ischemia in older individuals. The present findings may provide a partial explain ation for why men are more prone to develop both physiological (training) and pathological (hypertensive) LVH (12, 46). Both types have been linked to altered myocardial substrate utilization and to variations in PPAR-{alpha} gene expression (22, 28). Moreover, MFAO also is reported to be an independent negative predictor of increased LV mass (11). Thus, the increased delivery of fatty acids in women that occurs as a result of exercise training may prevent physiological myocardial hypertrophy. Combined with the findings of the present study, these data suggest that, at least in the case of physiological LVH, hypertrophy may depend on a permissively low fatty oxidation state predominantly seen in men. Although physiological LVH was not induced in the present study, this result is likely attributable to the time frame and intensity of the EET regimen, as volunteers were selected for their sedentary status. Whether clinical interventions that alter myocardial fatty acid metabolism can affect the hypertrophic response to exercise or hypertension remains to be determined.

Conclusions. This study demonstrates that EET in older individuals increases the myocardial glucose response to stress, with no detectible gender difference. However, compared with older men, older women are more likely to improve the myocardial fatty acid metabolic response to β-adrenergic stimulation.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institutes of Health Grants K23-HL-077179 (to P. F. Soto), RO1-AG-154666 (to R. J. Gropler), RR-00036 (General Clinical Research Center), and DK-56341 (Clinical Nutrition Research Unit); by American Heart Association Grant 02255732 (to P. F. Soto); and by The Robert Wood Johnson Foundation Amos Medical Faculty Development Program Award (to P. F. Soto).


   ACKNOWLEDGMENTS
 
The authors thank Carrie Stetz and Robert Schuh for editorial assistance and Debi DeLano, Theresa Butler, and Shalonda Scott for technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. F. Soto, Cardiovascular Div., Washington Univ. School of Medicine, Campus Box 8225, 660 S. Euclid Ave., St. Louis, MO 63110 (e-mail: sotop{at}mir.wustl.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
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  1. Bearden SE. Advancing age produces sex differences in vasomotor kinetics during and after skeletal muscle contraction. Am J Physiol Regul Integr Comp Physiol 293: R1274–R1279, 2007.[Abstract/Free Full Text]
  2. Berggren JR, Hulver MW, Houmard JA. Fat as an endocrine organ: influence of exercise. J Appl Physiol 99: 757–764, 2005.[Abstract/Free Full Text]
  3. Bergmann SR, Herrero P, Markham J, Herrero P. Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography. J Am Coll Cardiol 14: 639–652, 1989.[Abstract]
  4. Bergmann SR, Weinheimer CJ, Markham J, Herrero P. Quantitation of myocardial fatty acid metabolism using positron emission tomography. J Nucl Med 37: 1723–1730, 1996.[Abstract/Free Full Text]
  5. Buck A, Wolpers HG, Hutchins GD, Savas V, Nguyen N, Schwaiger M. Effect of carbon-11-acetate recirculation on estimates of myocardial oxygen consumption by PET. J Nucl Med 32: 1950–1957, 1991.[Abstract/Free Full Text]
  6. Coggan AR, Spina RJ, King DS, Rogers MA, Brown M, Nemeth PM, Holloszy JO. Skeletal muscle adaptations to endurance training in 60- to 70-yr-old men and women. J Appl Physiol 72: 1780–1786, 1992.[Abstract/Free Full Text]
  7. Cox JH, Cortright RN, Dohm GL, Houmard JA. Effect of aging on response to exercise training in humans: skeletal muscle GLUT-4 and insulin sensitivity. J Appl Physiol 86: 2019–2025, 1999.[Abstract/Free Full Text]
  8. Crampes F, Riviere D, Beauville M, Marceron M, Garrigues M. Lipolytic response of adipocytes to epinephrine in sedentary and exercise-trained subjects: sex-related differences. Eur J Appl Physiol 59: 249–255, 1989.[CrossRef][Web of Science]
  9. d'Agostino C, Labinskyy V, Lionetti V, Chandler MP, Lei B, Matsuo K, Bellomo M, Xu X, Hintze TH, Stanley WC, Recchia FA. Altered cardiac metabolic phenotype after prolonged inhibition of NO synthesis in chronically instrumented dogs. Am J Physiol Heart Circ Physiol 290: H1721–H1726, 2006.[Abstract/Free Full Text]
  10. De Angelis KL, Oliveira AR, Werner A, Bock P, Bello-Klein A, Fernandes TG, Bello AA, Irigoyen MC. Exercise training in aging: hemodynamic, metabolic, and oxidative stress evaluations. Hypertension 30: 767–771, 1997.[Abstract/Free Full Text]
  11. de las Fuentes L, Herrero P, Peterson LR, Kelly DP, Gropler RJ, Davila-Roman V. Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease. Hypertension 41: 83–87, 2003.[Abstract/Free Full Text]
  12. de Simone G, Devereux R, Daniels SR, Meyer RA. Gender differences in left ventricular growth. Hypertension 26: 979–983, 1995.[Abstract/Free Full Text]
  13. Dela F, Milkines KJ, Larsen JJ, Galbo H. Training-induced enhancement of insulin action in human skeletal muscle: the influence of aging. J Gerontol A Biol Sci Med Sci 51: B247–B252, 1996.[Abstract]
  14. Ehsani AA, Ogawa T, Miller TR, Spina RJ, Jilka SM. Exercise training improves left ventricular systolic function in older men. Circulation 83: 96–103, 1991.[Abstract/Free Full Text]
  15. Ehsani AA, Spina RJ, Peterson LR, Rinder MR, Glover KL, Villareal DT, Binder EF, Holloszy JO. Attenuation of cardiovascular adaptations to exercise in frail octogenarians. J Appl Physiol 95: 1781–1788, 2003.[Abstract/Free Full Text]
  16. Evans EM, Racette SB, Peterson LR, Villareal DT, Greiwe JS, Holloszy JO. Aerobic power and insulin action improve in response to endurance exercise training in healthy 77–87 yr olds. J Appl Physiol 98: 40–45, 2005.[Abstract/Free Full Text]
  17. Evans EM, Van Pelt RE, Binder EF, Williams DB, Ehsani AA, Kohrt WM. Effects of HRT and exercise training on insulin action, glucose tolerance and body composition in older women. J Appl Physiol 90: 2033–2040, 2001.[Abstract/Free Full Text]
  18. Gokhale R, Chandrashekara S, Vasanthakumar KC. Cytokine response to strenuous exercise in athletes and non-athletes–an adaptive response. Cytokine 40: 123–127, 2007.[CrossRef][Web of Science][Medline]
  19. Haykowsky M, McGavock J, Muhll IV, Koller M, Mandic S, Welsh R, Taylor D. Effect of exercise training on peak aerobic power, left ventricular morphology and muscle strength in healthy older women. J Gerontol A Biol Sci Med Sci 60: 307–311, 2005.[Abstract/Free Full Text]
  20. Herrero P, Peterson LR, McGill JB, Matthew S, Lesniak D, Dence C, Gropler RJ. Increase myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol 47: 598–604, 2006.[Abstract/Free Full Text]
  21. Herrero P, Soto PF, Dence CS, Kisrieva-Ware Z, DeLano DA, Peterson LR, Gropler RJ. Impact of hormone replacement on myocardial fatty acid metabolism: potential role of estrogen. J Nucl Cardiol 12: 574–581, 2005.[CrossRef][Web of Science][Medline]
  22. Herrero P, Weinheimer CJ, Dence C, Oellerich WF, Gropler RJ. Quantification of myocardial glucose utilization by positron emission tomography and 1-11C-glucose. J Nucl Cardiol 9: 5–14, 2002.[CrossRef][Web of Science][Medline]
  23. Hickey MS, Houmard JA, Considine RV, Tyndall GL, Midgette JB, Gavigan KE, Weidner ML, McCammon MR, Israel RG, Caro JF. Gender-dependent effects of exercise training on serum leptin levels in humans. Am J Physiol Endocrinol Metab 272: E562–E566, 1997.[Abstract/Free Full Text]
  24. Horton T, Braun B. Sex-based differences in substrate metabolism. Adv Mol Cell Biol 34: 209–227, 2004.[CrossRef]
  25. Hossak KF, Bruce RA. Maximal cardiac function in sedentary normal men and women: comparison of age-related changes. J Appl Physiol 53: 799–804, 1982.[Abstract/Free Full Text]
  26. Hughes VA, Fiatarone MA, Fielding RA, Ferrara CM, Elahi D, Evans WJ. Long-term effects of a high-carbohydrate diet and exercise on insulin action in older subjects with impaired glucose tolerance. Am J Clin Nutr 62: 426–433, 1995.[Abstract/Free Full Text]
  27. Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Takanashi M, Irukayama-Tomobe Y, Sakai S, Ohmori H, Matsuda M, Yamaguchi I. Aging-induced decrease in the PPAR-{alpha} level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol 283: H1750–H1760, 2002.[Abstract/Free Full Text]
  28. Jamshidi Y, Montgomery HE, Hense H, Myerson SG, Torra IP, Staels B, World MJ, Doering A, Erdmann J, Hengstenberg C, Humphries SE, Schunkert H, Flavell DM. Peroxisome proliferator-activated receptor {alpha} gene regulates left ventricular growth in response to exercise and hypertension. Circulation 105: 950–955, 2002.[Abstract/Free Full Text]
  29. Kahn SE, Larson VG, Beard JC. Effects of exercise on insulin action, glucose tolerance, and insulin secretion. Am J Physiol Endocrinol Metab 258: E937–E943, 1990.[Abstract/Free Full Text]
  30. Kates AM, Herrero P, Dence CS, Soto PF, Srinivasan M, DeLano DG, Gropler RJ. Impact of aging on substrate metabolism by the human heart. J Am Coll Cardiol 41: 293–299, 2003.[Abstract/Free Full Text]
  31. Kohrt WM, Kirwan JP, Staten MA, Bourey RE, King DS, Holloszy JO. Insulin resistance in aging is related to abdominal obesity. Diabetes 42: 273–281, 1993.[Abstract]
  32. Kohrt WM, Malley MT, Coggan AR, Spina RJ, Ogawa T, Ehsani AA, Bourey RE, Martin WHI, Holloszy JO. Effects of gender, age, and fitness level on the responses of Formula 3O2max to training in 60–71 yr olds. J Appl Physiol 71: 2004–2011, 1991.[Abstract/Free Full Text]
  33. Laughlin MH, Schrage WG, McAllister RM, Garverick HA, Jones AW. Interaction of gender and exercise training: vasomotor reactivity of porcine skeletal muscle arteries. J Appl Physiol 90: 216–227, 2001.[Abstract/Free Full Text]
  34. Maeda S, Miyauchi T, Kakiyama T, Sugawara J, Iemitsu M, Irukayama-Tomobe Y, Murakami H, Kumagai Y, Kuno S, Matsuda M. Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans. Life Sci 69: 1005–1016, 2001.[CrossRef][Web of Science][Medline]
  35. Marcell TJ, McAuley KA, Traustadottir T, Reaven PD. Exercise training is not associated with improved levels of C-reactive protein or adiponectin. Metabolism 52: 939–944, 2005.
  36. Mazzeo RS, Brooks GA, Horvath SM. Effects of age on metabolic responses to endurance training in rats. J Appl Physiol 57: 1369–1374, 1984.[Abstract/Free Full Text]
  37. Pruchnic R, Katsiaras A, He J, Kelley DE, Winters C, Goodpaster BH. Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am J Physiol Endocrinol Metab 287: E857–E862, 2004.[Abstract/Free Full Text]
  38. Recchia FA, Osorio JC, Chandler MP, Xu X, Panchal AR, Lopaschuk GD, Hintze TH, Stanley WC. Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. Am J Physiol Endocrinol Metab 282: E197–E206, 2002.[Abstract/Free Full Text]
  39. Richey PA, Brown SP. Pathological versus physiological left ventricular hypertrophy: a review. J Sports Sci 16: 129–141, 1998.[CrossRef][Web of Science][Medline]
  40. Scheuer J. Cardiovascular adaptations to physical training. Annu Rev Physiol 39: 221–251, 1977.[CrossRef][Web of Science][Medline]
  41. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, Silverman NH, Tajik AJ. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 2: 358–367, 1989.[Medline]
  42. Short KR, Vittone JL, Bigelow ML, Proctor DN, Nair KS. Age and aerobic exercise training effects on whole body and muscle protein metabolism. Am J Physiol Endocrinol Metab 286: E92–E101, 2004.[Abstract/Free Full Text]
  43. Sial S, Coggan AR, Hickner RC, Klein S. Training-induced alterations in fat and carbohydrate metabolism during exercise in elderly subjects. Am J Physiol Endocrinol Metab 274: E785–E790, 1998.[Abstract/Free Full Text]
  44. Soto PF, Herrero P, Kates AM, Dence CS, Ehsani AA, Davila-Roman V, Schechtman KB, Gropler RJ. Impact of aging on myocardial metabolic response to dobutamine. Am J Physiol Heart Circ Physiol 285: H2158–H2164, 2003.[Abstract/Free Full Text]
  45. Spina RJ, Miller TR, Bogenhagen WH, Schechtman KB, Ehsani AA. Gender-related differences in left ventricular filling dynamics in older subjects after endurance exercise training. J Gerontol A Biol Sci Med Sci 51: B232–B237, 1996.[Abstract]
  46. Spina RJ, Ogawa T, Kohrt WM, Martin WHI, Holloszy JO, Ehsani AA. Differences in cardiovascular adaptations to endurance exercise training between older men and women. J Appl Physiol 75: 849–855, 1993.[Abstract/Free Full Text]
  47. Spina RJ, Rashid S, Davila-Roman VG, Ehsani AA. Adaptations in β-adrenergic cardiovascular responses to training in older women. J Appl Physiol 89: 2300–2305, 2000.[Abstract/Free Full Text]
  48. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85: 1093–1129, 2005.[Abstract/Free Full Text]
  49. Starnes JW, Beyer RE, Edington DW. Myocardial adaptations to endurance exercise in aged rats. Am J Physiol Heart Circ Physiol 245: H560–H566, 1983.[Abstract/Free Full Text]
  50. Stolen KQ, Kemppainen J, Kalliokoski KK, Luotolahti M, Viljanen T, Nuutila P, Knuuti J. Exercise training improves insulin-stimulated myocardial glucose uptake in patients with dilated cardiomyopathy. J Nucl Cardiol 10: 447–455, 2003.[CrossRef][Web of Science][Medline]
  51. Toth MJ, Gardner AW, Arciero PJ, Calles-Escandon J. Gender differences in fat oxidation and sympathetic nervous system activity at rest and during submaximal exercise in older individuals. Clin Sci 95: 59–66, 1998.[CrossRef][Web of Science][Medline]
  52. Van Hall R, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88: 3005–3010, 2003.[Abstract/Free Full Text]
  53. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8: 1288–1295, 2002.[CrossRef][Web of Science][Medline]
  54. Young ME, Razeghi P, Cedars AM, Guthrie PH, Taegtmeyer H. Intrinsic diurnal variations in cardiac metabolism and contractile function. Circ Res 89: 1199–1208, 2001.[Abstract/Free Full Text]




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