Sex modifies exercise and cardiac adaptation in mice

Abstract

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. Ca 2ϩ /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-3␤ (GSK-3␤) 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 mitogenactivated 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. hypertrophy; myocyte signaling; workload; glycogen; calmodulin DESPITE INCREASING KNOWLEDGE of the mechanisms of cardiac adaptation to increased workload, there are significant sex/ gender differences that remain poorly understood. For example, in response to pathological stimuli such as systemic hypertension or aortic stenosis, women respond with more left ventricular hypertrophy and augmented contractility than men (51, 54), whereas men progress to poor contractility, chamber dilation, and wall thinning (7,11,24,39,50). Yet in the face of ischemic heart disease, females fare worse than their male counterparts (12,14,21).Physiological stimuli such as exercise can also elicit a sexually dimorphic cardiac response. Despite conflicting reports on the functional impact of exercise on the heart, it is apparent that there is differential remodeling between the sexes in response to aerobic exercise (16,49). Moreover, the sexually dimorphic cardiac response to exercise likely depends on the type of activity performed (aerobic vs. anaerobic, chronic vs. acute) as demonstrated in exercise-trained male and female rats. Male and female animals exercised by treadmill running have similar heart mass compared with sedentary controls (42, 44). In both sexes, ...

Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy

“…Exercise also had a beneficial effect on the apoptotic index in the CryAB R120G hearts (16) with both TUNELpositive nuclei and activated caspase-3 levels reduced. These results are in agreement with previous studies indicating the antiapoptotic effect of exercise training (30)(31)(32). Although voluntary exercise had no effect on the functional parameters measured by echocardiography, these data are consistent with a clinical trial in which 100 chronic HF patients were enlisted.…”

“…It is unclear what the outcome of more intensive, forced exercise regimens such as swimming or running on a motorized, incline treadmill would be. Under certain conditions, exercise is clearly beneficial, and, in a hypertrophic cardiomyopathic mouse model carrying a mutation in the gene that encodes the predominant cardiac myosin heavy chain, voluntary cage wheel running prevented onset of cardiac pathology and ameliorated existing pathology when initiated in older animals (30). However, intense exercise is associated with sudden cardiac death in symptomatic and asymptomatic heart disease resulting from different etiologies (34), and, for humane reasons, we have not subjected obviously ill mice to high-stress exercise.…”

Wheel running in female C57BL/6J mice: impact of oestrus and dietary fat and effects on sleep and body mass

“…9 Mice also exhibit sexual dimorphism with respect to both wheel and treadmill running. [10][11][12] De Bono et al 11 alluded to an effect of oestrus cycle on daily running distance and a similar effect was seen in pilot studies in our laboratory (data not shown).…”

A Method to Study the Impact of Chemically-induced Ovarian Failure on Exercise Capacity and Cardiac Adaptation in Mice

“…We did not see significant differences in exercise performance measured by average daily time, distance, and speed on the cage wheel between VCD-and vehicle-treated groups in either C57BL/6 or B6C3F1 mouse strain ( Figure 4A). The calculated wheel-running speeds gradually increased over the 4-week running period as previously shown 16 , but were not significantly different between experimental groups. These studies indicate the impact of VCD-induced ovarian failure on voluntary cage wheel exercise transcends at least 2 mouse strains.…”

“…We have previously shown that voluntary cage wheel exercise induces an increase in cardiac mass 16 . Here, we also show cardiac hypertrophy in response to cage wheel exercise measured by absolute heart weight (HW) and HW normalized to tibial length (TL) ( Table 1).…”