Circadian misalignment occurs with age, jet lag, and shift work, leading to maladaptive health outcomes including cardiovascular diseases. Despite the strong link between circadian disruption and heart disease, the cardiac circadian clock is poorly understood, prohibiting identification of therapies to restore the broken clock. Exercise is the most cardioprotective intervention identified to date and has been suggested to reset the circadian clock in other peripheral tissues. Here, we tested the hypothesis that conditional deletion of core circadian gene Bmal1 would disrupt cardiac circadian rhythm and function and that this disruption would be ameliorated by exercise. To test this hypothesis, we generated a transgenic mouse with spatial and temporal deletion of Bmal1 only in adult cardiac myocytes (Bmal1 cardiac knockout [cKO]). Bmal1 cKO mice demonstrated cardiac hypertrophy and fibrosis concomitant with impaired systolic function. This pathological cardiac remodeling was not rescued by wheel running. While the molecular mechanisms responsible for the profound cardiac remodeling are unclear, it does not appear to involve activation of the mammalian target of rapamycin (mTOR) signaling or changes in metabolic gene expression. Interestingly, cardiac deletion of Bmal1 disrupted systemic rhythms as evidenced by changes in the onset and phasing of activity in relationship to the light/dark cycle and by decreased periodogram power as measured by core temperature, suggesting cardiac clocks can regulate systemic circadian output. Together, we suggest a critical role for cardiac Bmal1 in regulating both cardiac and systemic circadian rhythm and function. Ongoing experiments will determine how disruption of the circadian clock causes cardiac remodeling in an effort to identify therapeutics to attenuate the maladaptive outcomes of a broken cardiac circadian clock.
Exercise is cardioprotective via distinct mechanisms in aged and young hearts.
Right ventricular (RV) function is the strongest predictor of survival in age-related heart failure as well as other clinical contexts in which aging populations suffer significant morbidity and mortality. However, despite the significance of maintaining RV function with age and disease, mechanisms of RV failure remain poorly understood and no RV-directed therapies exist. The anti-diabetic drug and AMP-activated protein kinase (AMPK) activator metformin protects against left ventricular dysfunction, suggesting cardioprotective properties may translate to the RV. Here, we aimed to understand the impact of advanced age on pulmonary hypertension induced right ventricular dysfunction. We further aimed to test whether metformin is cardioprotective in the RV and if the protection afforded by metformin requires cardiac AMPK. We used a murine model of PH by exposing adult (4-6 months) and aged (18 months) male and female mice to hypobaric hypoxia (HH) for 4 weeks. Cardiopulmonary remodeling was exacerbated in aged mice compared to adult as evidenced by elevated RV weight and impaired RV systolic function. Metformin attenuated HH induced RV dysfunction but only in adult male mice. Metformin still protected the adult male RV even in the absence of cardiac AMPK. Together, we suggest that aging exacerbates PH-induced RV remodeling and that metformin may represent a therapeutic option for this disease in a sex and age-dependent, but in an AMPK independent manner. Ongoing efforts are aimed at elucidating the molecular basis for RV remodeling as well as delineating the mechanisms of cardioprotection provided by metformin in the absence of cardiac AMPK.
Cardiovascular disease is an enormous public health problem, particularly in older populations. Exercise is the most potent cardioprotective intervention identified to date, with exercise in the juvenile period potentially imparting greater protection given the plasticity of the developing heart. To test the hypothesis that voluntary wheel running early in life would be cardioprotective later in life when risk for disease is high, we provided male and female juvenile (3-week old) mice access to a running wheel for two weeks. Mice then returned to a home cage to age to adulthood (4-6 months) before exposure to isoproterenol (ISO) to induce cardiac stress. Cardiac function and remodeling were compared to sedentary control mice, sedentary mice exposed to ISO, and mice that exercised in adulthood immediately before ISO. Early in life activity protected against ISO-induced stress as evidenced by attenuated cardiac mass, myocyte size, and fibrosis compared to sedentary ISO. ISO-induced changes in cardiac function were ameliorated in male mice that engaged in wheel running, with ejection fraction and fractional shortening reversed to control values. Adrenergic receptor expression was downregulated in juvenile male runners. This suppression persisted in adulthood following ISO, providing a putative mechanism by which exercise in the young male heart provides resilience to cardiac stress later in life. Together, we show that activity early in life induces persistent cardiac changes that attenuate ISO-induced stress in adulthood. Identification of the mechanisms by which early in life exercise is protective will yield valuable insight into how exercise is medicine across the life-course.
Cardiovascular disease continues to be a major cause of morbidity and mortality, particularly in aging populations. Exercise is amongst the most cardioprotective interventions identified to date, with early in life exercise such as during the juvenile period potentially imparting even more cardioprotective outcomes due to the plasticity of the developing heart. To test the hypothesis that juvenile exercise would impart later in life cardioprotection, we exercised juvenile male and female mice via voluntary wheel running from 3-5 weeks of age and then exposed them to cardiac stress by isoproterenol (ISO) at 4-6 and 18 months of age in adulthood and older age, respectively. We compared cardiac function and remodeling to sedentary control animals, sedentary animals who received ISO, and adult and aged mice that exercised for two weeks immediately before ISO exposure. Juvenile mice engaged in voluntarily wheel running, with male mice running 1.3 ± 0.8 km and female mice 2.8 ± 1.0 km a day. Echocardiography suggested that these juvenile animals underwent running-induced cardiac remodeling as evidenced by higher ejection fraction and stroke volume compared to sedentary controls. Exercise in the juvenile period attenuated ISO-induced cardiac hypertrophy and remodeling later in life compared to sedentary animals and those that exercised immediately before ISO administration. The mechanisms by which early versus late exercise is protective in adult and aged mice are under investigation. Further ongoing work will identify the adaptations induced by exercise in the juvenile heart that may help improve cardiac aging.
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