Objective: In contrast to age-matched men, endurance exercise training is not consistently associated with enhanced endothelial function in estrogen-deficient postmenopausal women. We determined whether endurance exercise training improves endothelial function in postmenopausal women treated with estrogen. In a substudy, we determined if oxidative stress is mechanistically linked to endothelial function adaptations to endurance exercise training. Participants and Design: Brachial artery flow-mediated dilation (FMD) was measured in 36 sedentary, estrogen-deficient postmenopausal women (45–65 y) at study entry (baseline), after 12 weeks of either placebo, oral (1 mg/d) estradiol, or transdermal estradiol (0.05 mg/d) (randomized), and after an additional 12 weeks of continued estradiol or placebo treatment with concurrent endurance exercise training. In subgroups of women, FMD also was measured during the infusion of ascorbic acid at baseline and following estradiol/placebo plus endurance exercise training, and in seven habitually endurance-trained estrogen-deficient controls. Results: FMD increased in the estrogen-treated groups (both P < .01) after 12 weeks and remained unchanged in placebo. FMD further increased following 12 weeks of endurance exercise training in estrogen-treated (both P < .025), but not placebo-treated women (P = .55). In the substudy, baseline FMD was similar between sedentary and endurance-trained controls. Ascorbic acid increased FMD at baseline in sedentary women and endurance-trained controls, and following endurance exercise training in placebo-treated, but not in estrogen-treated women. Conclusions: Estrogen status appears to play an important modulatory role in improvements in endothelial function with endurance exercise training in postmenopausal women. The restored endurance exercise training adaptation in estrogen-treated postmenopausal women may be related to mitigation of oxidative stress.

How an individual's sex and genetic background modify cardiac adaptation to increased workload is a topic of great interest. We systematically evaluated morphological and physiological cardiac adaptation in response to voluntary and forced exercise. We found that sex/gender is a dominant factor in exercise performance (in two exercise paradigms and two mouse strains) and that females of one of these strains have greater capacity to increase their cardiac mass in response to similar amounts of exercise. To explore the biochemical mechanisms for these differences, we examined signaling pathways previously implicated in cardiac hypertrophy. Ca²⁺/calmodulin-dependent protein kinase (CaMK) activity was significantly greater in males compared with females and increased after voluntary cage-wheel exposure in both sexes, but the proportional increase in CaMK activity was twofold higher in females compared with males. Phosphorylation of glycogen synthase kinase-3β (GSK-3β) was evident after 7 days of cage-wheel exposure in both sexes and remained elevated in females only by 21 days of exercise. Despite moderate increases in myocyte enhancer factor-2 (a downstream effector of CaMK) transcriptional activity and phosphorylation of Akt with exercise, there were no sex differences. Mitogen-activated protein kinase signaling components (p38 mitogen-activated protein kinase and extracellular regulated kinase 1/2) were not different between male and female mice and were not affected by exercise. We conclude that females have increased exercise capacity and increased hypertrophic response to exercise. We have also identified sex-specific differences in hypertrophic signaling within the cardiac myocyte that may contribute to sexual dimorphism in exercise and cardiac adaptation to exercise.

Hypertrophic cardiomyopathy (HCM) is the most common form of sudden death in young competitive athletes. However, exercise has also been shown to be beneficial in the setting of other cardiac diseases. We examined the ability of voluntary exercise to prevent or reverse the phenotypes of a murine model of HCM harboring a mutant myosin heavy chain (MyHC). No differences in voluntary cage wheel performance between nontransgenic (NTG) and HCM male mice were seen. Exercise prevented fibrosis, myocyte disarray, and induction of “hypertrophic” markers including NFAT activity when initiated before established HCM pathology. If initiated in older HCM animals with documented disease, exercise reversed myocyte disarray (but not fibrosis) and “hypertrophic” marker induction. In addition, exercise returned the increased levels of phosphorylated GSK-3β to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels. Exercise in HCM mice also favorably impacted components of the apoptotic signaling pathway, including Bcl-2 (an inhibitor of apoptosis) and procaspase-9 (an effector of apoptosis) expression, and caspase-3 activity. Remarkably, there were no differences in mortality between exercised NTG and HCM mice. Thus, not only was exercise not harmful but also it was able to prevent and even reverse established cardiac disease phenotypes in this HCM model.

Increased endothelin-1–mediated vasoconstrictor tone has been linked to the etiology of a number of pathologies associated with human aging, including hypertension, congestive heart failure, and coronary artery disease. However, it is currently unclear whether aging, per se, is associated with enhanced endothelin-1 system activity. We hypothesized that endothelin-1 vasoconstrictor activity is greater in healthy older compared with young men and that regular aerobic exercise is an effective intervention for reducing endothelin-1 vasoconstrictor tone in older previously sedentary men. Forearm blood flow (plethysmography) responses to intra-arterial infusion of endothelin-1 (5 pmol/min; for 20 minutes) and selective (BQ-123; 100 nmol/min; for 60 minutes) and nonselective (BQ-123+BQ-788; 100 nmol/min; for 60 minutes) endothelin-1 receptor blockade were determined in 28 healthy, sedentary men: 13 younger (age: 27±1 years) and 15 older (age: 62±2 years). The vasoconstrictor response to endothelin-1 was significantly blunted (≈65%) in the older versus younger men. In response to BQ-123, resting forearm blood flow increased (≈20%; P <0.05) in the older but not in the younger men. The addition of BQ-788 to BQ-123 did not significantly affect the blood flow responses to BQ-123 in either group. Eight of the 15 older sedentary men completed a 3-month aerobic exercise intervention. After the intervention, the vasoconstrictor response to endothelin-1 was markedly increased (225%; P <0.05), whereas BQ-123 resulted in modest vasoconstriction in the previously sedentary older men. These results demonstrate that endothelin-1–mediated vasoconstrictor tone increases with age in healthy men but can be alleviated with regular aerobic exercise.

Negative alterations of mitochondria are known to occur in heart failure (HF). This study investigated the novel mitochondrial-targeted therapeutic agent elamipretide on mitochondrial and supercomplex function in failing human hearts ex vivo. Freshly explanted failing and nonfailing ventricular tissue from children and adults was treated with elamipretide. Mitochondrial oxygen flux, complex (C) I and CIV activities, and in-gel activity of supercomplex assembly were measured. Mitochondrial function was impaired in the failing human heart, and mitochondrial oxygen flux, CI and CIV activities, and supercomplex-associated CIV activity significantly improved in response to elamipretide treatment. Elamipretide significantly improved failing human mitochondrial function.