Effects of High-Intensity Exercise Training on Adipose Tissue Mass, Glucose Uptake and Protein Content in Pre- and Post-menopausal Women.

The menopausal transition is accompanied by changes in adipose tissue storage, leading to an android body composition associated with increased risk of type 2 diabetes and cardiovascular disease in post-menopausal women. Estrogens probably affect local adipose tissue depots differently. We investigated how menopausal status and exercise training influence adipose tissue mass, adipose tissue insulin sensitivity and adipose tissue proteins associated with lipogenesis/lipolysis and mitochondrial function. Healthy, normal-weight pre- (n = 21) and post-menopausal (n = 20) women participated in high-intensity exercise training three times per week for 12 weeks. Adipose tissue distribution was determined by dual-energy x-ray absorptiometry and magnetic resonance imaging. Adipose tissue glucose uptake was assessed by positron emission tomography/computed tomography (PET/CT) by the glucose analog [18F]fluorodeoxyglucose ([18F]FDG) during continuous insulin infusion (40 mU·m-2·min-1). Protein content associated with insulin signaling, lipogenesis/lipolysis, and mitochondrial function were determined by western blotting in abdominal and femoral white adipose tissue biopsies. The mean age difference between the pre- and the post-menopausal women was 4.5 years. Exercise training reduced subcutaneous (~4%) and visceral (~6%) adipose tissue masses similarly in pre- and post-menopausal women. Insulin-stimulated glucose uptake, assessed by [18F]FDG-uptake during PET/CT, was similar in pre- and post-menopausal women in abdominal, gluteal, and femoral adipose tissue depots, despite skeletal muscle insulin resistance in post- compared to pre-menopausal women in the same cohort. Insulin-stimulated glucose uptake in adipose tissue depots was not changed after 3 months of high-intensity exercise training, but insulin sensitivity was higher in visceral compared to subcutaneous adipose tissue depots (~139%). Post-menopausal women exhibited increased hexokinase and adipose triglyceride lipase content in subcutaneous abdominal adipose tissue. Physical activity in the early post-menopausal years reduces abdominal obesity, but insulin sensitivity of adipose tissue seems unaffected by both menopausal status and physical activity.

Cardiac perfusion and function after high-intensity exercise training in late premenopausal and recent postmenopausal women: an MRI study.

We examined the influence of recent menopause and aerobic exercise training in women on myocardial perfusion, left ventricular (LV) dimension, and function. Two groups (n = 14 each) of healthy late premenopausal (50.2 ± 2.1 yr) and recent postmenopausal (54.2 ± 2.8 yr) women underwent cardiac magnetic resonance imaging (cMRI) at baseline and after 12 wk of high-intensity aerobic training. Measurements included LV morphology, systolic function, and myocardial perfusion at rest and during an adenosine stress test. At baseline, resting myocardial perfusion was lower in the postmenopausal than the premenopausal group (77 ± 3 vs. 89 ± 3 ml·100 g-1·min-1; P = 0.01), while adenosine-induced myocardial perfusion was not different (P = 0.81). After exercise training, resting myocardial perfusion was lower in both groups (66 ± 2; P = 0.002 vs. 81 ± 3 ml·100 g-1·min-1; P = 0.03). The adenosine-induced change in myocardial perfusion was lower in the groups combined (by 402 ± 17 ml·100 g-1·min-1; P = 0.02), and the adenosine-induced increase in heart rate was 10 ± 2 beats/min lower (P < 0.0001) in both groups after training. Normalization of myocardial perfusion using an estimate of cardiac work eliminated the differences in perfusion between the premenopausal and postmenopausal groups and the effect of training. Left ventricle mass was higher in both groups (P = 0.03; P = 0.006), whereas LV end-diastolic (P = 0.02) and stroke (P = 0.045) volumes were higher in the postmenopausal group after training. Twelve weeks of exercise training increased left ventricle mass and lowered resting and adenosine-induced myocardial perfusion, an effect that was likely related to cardiac work. The current data also suggest that the early menopausal transition has limited impact on cardiac function and structure. NEW & NOTEWORTHY This study provides for the first time estimates of myocardial perfusion in late premenopausal and recent postmenopausal women before and after a period of intense aerobic training. Resting myocardial perfusion was lower in postmenopausal than premenopausal women. Training lowered myocardial resting and stress perfusion in both groups, an effect that was likely influenced by the lower heart rate.

Effect of menopause and exercise training on plasma apolipoprotein M and sphingosine-1-phosphate.

The axis of apolipoprotein M (apoM) and sphingosine-1-phosphate (S1P) is of importance to plasma lipid levels, endothelial function, and development of atherosclerosis. Menopause is accompanied by dyslipidemia and an increased risk of atherosclerosis, which can be lowered by exercise training. The aim of this study was to explore if effects of menopause and training are paralleled by changes in the apoM/S1P axis. Healthy, late premenopausal [ n = 38, age 49.2 (SD 2)] and recent postmenopausal [ n = 37, age 53.3 (SD 3)] women from the Copenhagen Women Study participated in a 3-mo, aerobic high-intensity exercise intervention. Before training, plasma apoM was higher in postmenopausal [1.08 µmol/l (SD 0.2)] compared with premenopausal [0.82 µmol/l (SD 0.2)] women ( P < 0.0001). Plasma S1P was similar in the two groups [0.44 µmol/l (SD 0.1) and 0.46 µmol/l (SD 0.1), respectively]. Thus, the pretraining S1P/apoM ratio was 26% lower in postmenopausal than premenopausal women ( P < 0.0001). After the training program, plasma apoM increased from 0.82 µmol/l (SD 0.2) to 0.90 µmol/l (SD 0.3) in premenopausal women and from 1.08 µmol/l (SD 0.2) to 1.16 µmol/l (SD 0.3) in postmenopausal women ( P < 0.05). Plasma S1P increased from 0.44 µmol/l (SD 0.1) to 0.47 µmol/l (SD 0.1) in premenopausal women and from 0.46 µmol/l (SD 0.1) to 0.48 µmol/l (SD 0.1) in postmenopausal women ( P < 0.05). The results suggest that menopause is accompanied by higher plasma apoM but not S1P concentrations and that exercise training increases plasma apoM and S1P in healthy middle-aged women irrespective of menopausal status. NEW & NOTEWORTHY The apolipoprotein M/sphingosine-1-phosphate (apoM/S1P) complex is involved in maintaining a healthy endothelial barrier function. Our study is the first, to our knowledge, to show how menopause affects the apoM/S1P axis. The results suggest that menopause is accompanied by higher plasma apoM but not S1P concentrations. Second, to our knowledge the study is also the first to show that exercise training increases both apoM/S1P in women irrespective of menopausal status.

Effects of menopause and high-intensity training on insulin sensitivity and muscle metabolism.

OBJECTIVE: To investigate peripheral insulin sensitivity and skeletal muscle glucose metabolism in premenopausal and postmenopausal women, and evaluate whether exercise training benefits are maintained after menopause. METHODS: Sedentary, healthy, normal-weight, late premenopausal (n = 21), and early postmenopausal (n = 20) women were included in a 3-month high-intensity exercise training intervention. Body composition was assessed by magnetic resonance imaging and dual-energy x-ray absorptiometry, whole body glucose disposal rate (GDR) by hyperinsulinemic euglycemic clamp (40 mU/m/min), and femoral muscle glucose uptake by positron emission tomography/computed tomography, using the glucose analog fluorodeoxyglucose, expressed as estimated metabolic rate (eMR). Insulin signaling was investigated in muscle biopsies. RESULTS: Age difference between groups was 4.5 years, and no difference was observed in body composition. Training increased lean body mass (estimate [95% confidence interval] 0.5 [0.2-0.9] kg, P < 0.01) and thigh muscle mass (0.2 [-0.1 to 0.6] kg, P < 0.01), and decreased fat percentage (1.0 [0.5-1.5]%, P < 0.01) similarly in the two groups. The postmenopausal women had lower eMR in vastus lateralis muscle than the premenopausal women (-14.0 [-26.0 to -2.0] µmol/min/kg, P = 0.02), and tended to have lower eMR in femoral muscles (-11.2 [-22.7 to 0.4] µmol/min/kg, P = 0.06), and also GDR (-59.3 [-124.8 to 6.3] mg/min, P = 0.08), but increased similarly in both groups with training (eMR vastus lateralis muscle: 27.8 [19.6-36.0] µmol/min/kg, P < 0.01; eMR femoral muscle: 20.0 [13.1-26.7] µmol/min/kg, P < 0.01, respectively; GDR: 43.6 [10.4-76.9] mg/min, P = 0.01). Potential mechanisms underlying the training-induced increases in insulin sensitivity included increased expression of hexokinase (19.2 [5.0-24.7] AU, P = 0.02) and glycogen synthase (32.4 [15.0-49.8] AU, P < 0.01), and also increased insulin activation of Akt2 (20.6 [3.4-29.0], P = 0.03) and dephosphorylation of glycogen synthase (-41.8 [-82.9 to -0.7], P = 0.05). CONCLUSIONS: Insulin sensitivity was reduced in early postmenopausal women. However, postmenopausal women increased peripheral insulin sensitivity, skeletal muscle insulin-stimulated glucose uptake, and skeletal muscle mass to the same extent as premenopausal women after 3 months of high-intensity exercise training.

Cardiac Adaptations to High-Intensity Aerobic Training in Premenopausal and Recent Postmenopausal Women: The Copenhagen Women Study.

BACKGROUND: We examined the role of menopause on cardiac dimensions and function and assessed the efficacy of exercise training before and after menopause. METHODS AND RESULTS: Two groups of healthy premenopausal (n=36, 49.4±0.3 years) and postmenopausal (n=37, 53.5±0.5 years) women with no history of cardiovascular disease and with a mean age difference between groups of only 4 years were studied. Cardiac dimensions and systolic and diastolic function were determined by transthoracic echocardiography with tissue Doppler imaging and 2-dimensional speckle tracking. Measurements were performed at baseline and after a 12-week period of high-intensity aerobic cycle training. LV internal diastolic diameter and LV mass were similar in the 2 groups at baseline and increased by ≈2% to 8% (P=0.04-0.0007) with training in both groups. Left atrial end-diastolic and end-systolic volumes were similar for both groups and increased by 23% to 36% (P=0.0006-0.0001) with training. Systolic function assessed by mean global strain was similar in both groups at baseline and increased by ≈8% (P=0.0004) with training in the postmenopausal group. LV displacement increased by ≈3% (P=0.04) in the premenopausal women only. Diastolic function assessed by E/A ratio was similar at baseline and increased by ≈7% (P=0.01) in the premenopausal group and 11% (P=0.0001) in the postmenopausal group with training. CONCLUSIONS: These results suggest that training-induced cardiac adaptations are preserved in the early postmenopausal phase. Furthermore, the hormonal changes associated with the menopausal transition do not appear to affect cardiac dimensions and function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02135575.

Leg vascular and skeletal muscle mitochondrial adaptations to aerobic high-intensity exercise training are enhanced in the early postmenopausal phase.

KEY POINTS: Exercise training effectively improves vascular and skeletal muscle function; however, these effects of training may be blunted in postmenopausal women as a result of the loss of oestrogens. Accordingly, the capacity to deliver oxygen to the active muscles may also be impaired in postmenopausal women. In both premenopausal and recent postmenopausal women, exercise training was shown to improve leg vascular and skeletal muscle mitochondrial function. Interestingly, these effects were more pronounced in postmenopausal women. Skeletal muscle oxygen supply and utilization were similar in the two groups of women. These findings suggest that the early postmenopausal phase is associated with an enhanced capacity of the leg vasculature and skeletal muscle mitochondria to adapt to exercise training and that the ability to deliver oxygen to match the demand of the active muscles is preserved in the early phase following the menopausal transition. ABSTRACT: Exercise training leads to favourable adaptations within skeletal muscle; however, this effect of exercise training may be blunted in postmenopausal women as a result of the loss of oestrogens. Furthermore, postmenopausal women may have an impaired vascular response to acute exercise. We examined the haemodynamic response to acute exercise in matched pre- and postmenopausal women before and after 12 weeks of aerobic high intensity exercise training. Twenty premenopausal and 16 early postmenopausal (mean ± SEM: 3.1 ± 0.5 years after final menstrual period) women only separated by 4 years of age (mean ± SEM: 50 ± 0 years vs. 54 ± 1 years) were included. Before training, leg blood flow, O2 delivery, O2 uptake and lactate release during knee-extensor exercise were similar in pre- and postmenopausal women. Exercise training reduced (P < 0.05) leg blood flow, O2 delivery, O2 uptake, lactate release, blood pressure and heart rate during the same absolute workloads in postmenopausal women. These effects were not detected in premenopausal women. Quadriceps muscle protein contents of mitochondrial complex II, III and IV; endothelial nitric oxide synthase (eNOS); cyclooxygenase (COX)-1; COX-2; and oestrogen-related receptor α (ERRα) were increased (P < 0.05) with training in postmenopausal women, whereas only the levels of mitochondrial complex V, eNOS and COX-2 were increased (P < 0.05) in premenopausal women. These findings demonstrate that vascular and skeletal muscle mitochondrial adaptations to aerobic high intensity exercise training are more pronounced in recent post- compared to premenopausal women, possibly as an effect of enhanced ERRα signalling. Also, the hyperaemic response to acute exercise appears to be preserved in the early postmenopausal phase.

Effects of high-intensity training on cardiovascular risk factors in premenopausal and postmenopausal women.

BACKGROUND: Menopause is associated with increased risk of cardiovascular disease and the causal factors have been proposed to be the loss of estrogen and the subsequent alterations of the hormonal milieu. However, which factors contribute to the deterioration of cardiometabolic health in postmenopausal women is debated as the menopausal transition is also associated with increased age and fat mass. Furthermore, indications of reduced cardiometabolic adaptations to exercise in postmenopausal women add to the adverse health profile. OBJECTIVE: We sought to evaluate risk factors for type 2 diabetes and cardiovascular disease in late premenopausal and early postmenopausal women, matched by age and body composition, and investigate the effect of high-intensity training. STUDY DESIGN: A 3-month high-intensity aerobic training intervention, involving healthy, nonobese, late premenopausal (n = 40) and early postmenopausal (n = 39) women was conducted and anthropometrics, body composition, blood pressure, lipid profile, glucose tolerance, and maximal oxygen consumption were determined at baseline and after the intervention. RESULTS: At baseline, the groups matched in anthropometrics and body composition, and only differed by 4.2 years in age (mean [95% confidence limits] 49.2 [48.5-49.9] vs 53.4 [52.4-54.4] years). Time since last menstrual period for the postmenopausal women was (mean [95% confidence limits] 3.1 [2.6-3.7] years). Hormonal levels (estrogen, follicle stimulation hormone, luteinizing hormone) confirmed menopausal status. At baseline the postmenopausal women had higher total cholesterol (P < .001), low-density lipoprotein-cholesterol (P < .05), and high-density lipoprotein-cholesterol (P < .001) than the premenopausal women. The training intervention reduced body weight (P < .01), waist circumference (P < .01), and improved body composition by increasing lean body mass (P < .001) and decreasing fat mass (P < .001) similarly in both groups. Moreover, training resulted in lower diastolic blood pressure (P < .05), resting heart rate (P < .001), total cholesterol (P < .01), low-density lipoprotein-cholesterol (P < .01), total cholesterol/high-density lipoprotein-cholesterol index (P < .01), and improved plasma insulin concentration during the oral glucose tolerance test (P < .05) in both groups. CONCLUSION: Cardiovascular risk factors are similar in late premenopausal and early postmenopausal women, matched by age and body composition, with the exception that postmenopausal women have higher high- and low-density lipoprotein-cholesterol levels. A 3-month intervention of high-intensity aerobic training reduces risk factors for type 2 diabetes and cardiovascular disease to a similar extent in late premenopausal and early postmenopausal women.

Early Postmenopausal Phase Is Associated With Reduced Prostacyclin-Induced Vasodilation That Is Reversed by Exercise Training: The Copenhagen Women Study.

The postmenopausal phase is associated with an accelerated rate of rise in the prevalence of vascular dysfunction and hypertension; however, the mechanisms underlying these adverse vascular changes and whether exercise training can reverse the decline in vascular function remains unclear. We examined the function of the vascular prostanoid system in matched pre- and postmenopausal women before and after 12 weeks of exercise training. Twenty premenopausal and 16 early postmenopausal (3.1±0.5 [mean±SE] years after final menstrual period) women only separated by 4 (50±0 versus 54±1) years of age were included. Before the training period, the vasodilator response to intra-arterial infusion of either the prostacyclin analog epoprostenol or acetylcholine was lower (≈13%-41%; P<0.05) in the postmenopausal compared with the premenopausal women. Acetylcholine infusion induced a similar release of prostacyclin (6-keto prostaglandin F1a). To elucidate the role of vasoconstrictor prostanoids, acetylcholine infusion was combined with the cyclooxygenase inhibitor ketorolac and here the vascular response to acetylcholine was reduced to a similar extent in pre- and postmenopausal women. Exercise training increased (P<0.05) the vasodilator response to epoprostenol (≈100%-150%) and acetylcholine (≈100%-120%) infusion in the postmenopausal group. These findings demonstrate that the early postmenopausal phase is associated with a marked reduction in vascular function. Despite of a reduced sensitivity to prostacyclin, the overall balance between vasodilator and vasoconstrictor prostanoids does not seem to be altered. Exercise training can reverse the decline in vascular sensitivity to epoprostenol and acetylcholine, suggesting that beneficial vascular adaptations with exercise training are preserved in recent postmenopausal women.