Maternal exercise preserves offspring cardiovascular health via oxidative regulation of the ryanodine receptor.

OBJECTIVE: The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the metabolic health in adult offspring, but the effects of maternal exercise on offspring cardiovascular health have not been thoroughly investigated. METHODS: To determine the effects of maternal exercise on offspring cardiovascular health, female mice were fed a chow (C; 21% kcal from fat) or high-fat (H; 60% kcal from fat) diet and further subdivided into sedentary (CS, HS) or wheel exercised (CW, HW) prior to pregnancy and throughout gestation. Offspring were maintained in a sedentary state and chow-fed throughout 52 weeks of age and subjected to serial echocardiography and cardiomyocyte isolation for functional and mechanistic studies. RESULTS: High-fat fed sedentary dams (HS) produced female offspring with reduced ejection fraction (EF) compared to offspring from chow-fed dams (CS), but EF was preserved in offspring from high-fat fed exercised dams (HW) throughout 52 weeks of age. Cardiomyocytes from HW female offspring had increased kinetics, calcium cycling, and respiration compared to CS and HS offspring. HS offspring had increased oxidation of the RyR2 in cardiomyocytes coupled with increased baseline sarcomere length, resulting in RyR2 overactivity, which was negated in female HW offspring. CONCLUSIONS: These data suggest a role for maternal exercise to protect against the detrimental effects of a maternal high-fat diet on female offspring cardiac health. Maternal exercise improved female offspring cardiomyocyte contraction, calcium cycling, respiration, RyR2 oxidation, and RyR2 activity. These data present an important, translatable role for maternal exercise to preserve cardiac health of female offspring and provide insight on mechanisms to prevent the transmission of cardiovascular diseases to subsequent generations.

Chronic exercise improves hepatic acylcarnitine handling.

Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25.

Limb-girdle muscular dystrophy type R25 (LGMDR25) is caused by recessive mutations in BVES encoding a cAMP-binding protein, characterized by progressive muscular dystrophy with deteriorating muscle function and impaired cardiac conduction in patients. There is currently no therapeutic treatment for LGMDR25 patients. Here we report the efficacy and safety of recombinant adeno-associated virus 9 (AAV9)-mediated systemic delivery of human BVES driven by a muscle-specific promoter MHCK7 (AAV9.BVES) in BVES-knockout (BVES-KO) mice. AAV9.BVES efficiently transduced the cardiac and skeletal muscle tissues when intraperitoneally injected into neonatal BVES-KO mice. AAV9.BVES dramatically improved body weight gain, muscle mass, muscle strength, and exercise performance in BVES-KO mice regardless of sex. AAV9.BVES also significantly ameliorated the histopathological features of muscular dystrophy. The heart rate reduction was also normalized in BVES-KO mice under exercise-induced stress following systemic AAV9.BVES delivery. Moreover, intravenous AAV9.BVES administration into adult BVES-KO mice after the disease onset also resulted in substantial improvement in body weight, muscle mass, muscle contractility, and stress-induced heart rhythm abnormality. No obvious toxicity was detected. Taken together, these results provide the proof-of-concept evidence to support the AAV9.BVES gene therapy for LGMDR25.

Exercise training after myocardial infarction increases survival but does not prevent adverse left ventricle remodeling and dysfunction in high-fat diet fed mice.

AIMS: Aerobic exercise is an important component of rehabilitation after cardiovascular injuries including myocardial infarction (MI). In human studies, the beneficial effects of exercise after an MI are blunted in patients who are obese or glucose intolerant. Here, we investigated the effects of exercise on MI-induced cardiac dysfunction and remodeling in mice chronically fed a high-fat diet (HFD). MAIN METHODS: C57Bl/6 male mice were fed either a standard (Chow; 21% kcal/fat) or HFD (60% kcal/fat) for 36 weeks. After 24 weeks of diet, the HFD mice were randomly subjected to an MI (MI) or a sham surgery (Sham). Following the MI or sham surgery, a subset of mice were subjected to treadmill exercise. KEY FINDINGS: HFD resulted in obesity and glucose intolerance, and this was not altered by exercise or MI. MI resulted in decreased ejection fraction, increased left ventricle mass, increased end systolic and diastolic diameters, increased cardiac fibrosis, and increased expression of genes involved in cardiac hypertrophy and heart failure in the MI-Sed and MI-Exe mice. Exercise prevented HFD-induced cardiac fibrosis in Sham mice (Sham-Exe) but not in MI-Exe mice. Exercise did, however, reduce post-MI mortality. SIGNIFICANCE: These data indicate that exercise significantly increased survival after MI in a model of diet-induced obesity independent of effects on cardiac function. These data have important translational ramifications because they demonstrate that environmental interventions, including diet, need to be carefully evaluated and taken into consideration to support the effects of exercise in the cardiac rehabilitation of patients who are obese.

Brown adipose tissue prevents glucose intolerance and cardiac remodeling in high-fat-fed mice after a mild myocardial infarction.

BACKGROUND: Obesity increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes (T2D) after myocardial infarction (MI). Brown adipose tissue (BAT) is important to combat obesity and T2D, and increasing BAT mass by transplantation improves glucose metabolism and cardiac function. The objective of this study was to determine if BAT had a protective effect on glucose tolerance and cardiac function in high-fat diet (HFD) fed mice subjected to a mild MI. METHODS: Male C57BL/6 mice were fed a HFD for eight weeks and then divided into Sham (Sham-operated) and +BAT (mice receiving 0.1 g BAT into their visceral cavity). Sixteen weeks post-transplantation, mice were further subdivided into ±MI (Sham; Sham-MI; +BAT; +BAT-MI) and maintained on a HFD. Cardiac (echocardiography) and metabolic function (glucose and insulin tolerance tests, body composition and exercise tolerance) were assessed throughout 22 weeks post-MI. Quantitative PCR (qPCR) was performed to determine the expression of genes related to metabolic function of perigonadal adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), liver, heart, tibialis anterior skeletal muscle (TA); and BAT. RESULTS: +BAT prevented the increase in left ventricle mass (LVM) and exercise intolerance in response to MI. Similar to what is observed in humans, Sham-MI mice developed IGT post-MI, but this was negated in +BAT-MI mice. IGT was independent of changes in body composition. Genes involved in inflammation, insulin resistance, and metabolism were significantly altered in pgWAT, scWAT, and liver in Sham-MI mice compared to all other groups. CONCLUSIONS: BAT transplantation prevents IGT, the increase in LVM, and exercise intolerance following MI. MI alters the expression of several metabolic-related genes in WAT and liver in Sham-MI mice, suggesting that these tissues may contribute to the impaired metabolic response. Increasing BAT may be an important intervention to prevent the development of IGT or T2D and cardiac remodeling in obese patients post-MI.

The Heartwarming Effect of Brown Adipose Tissue.

Brown adipose tissue (BAT) is a metabolically active tissue that improves glucose metabolism and protects against the development of type 2 diabetes and obesity. However, the role of BAT to improve cardiovascular health has only recently been investigated. In this review, we discuss multiple mechanisms through which both the thermogenic and endocrine functions of BAT mediate cardiac health. ß-adrenergic stimulation activates the thermogenic function of BAT, resulting in reduced circulating lipids and glucose, and enhanced clearance of hepatic cholesterol-enriched remnants leading to reduced atherosclerotic region size. Additionally, the thermogenic role of BAT has been implicated in activation of the protein kinase B-extracellular-signal-regulated kinase (ERK) 1/2 pathway after myocardial infarction (MI), contributing to reduced injury size. The endocrine function of BAT has also been implicated to improve both systemic metabolic health and cardiac health. Specifically, the batokines fibroblast growth factor 21 (FGF21) and 12,13-diHOME improve cardiovascular health via reduced hypertension, hypertrophy and MI injury size (FGF21) or by directly improving cardiac function via calcium cycling (12,13-diHOME). Finally, we discuss relevant pharmacological treatment methods currently aiming to activate BAT, typically through sympathetic activation. SIGNIFICANCE STATEMENT: This mini-review discusses the role of BAT to improve cardiac health via thermogenic and endocrine effects in both rodents and humans and highlights the need for therapeutic methods which activate or mimic BAT activity.

A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function.

BACKGROUND: Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function. METHODS: To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1-/-) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease. RESULTS: Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1-/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease. CONCLUSIONS: Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.

Exercise-induced 3'-sialyllactose in breast milk is a critical mediator to improve metabolic health and cardiac function in mouse offspring.

Poor maternal environments, such as under- or overnutrition, can increase the risk for the development of obesity, type 2 diabetes and cardiovascular disease in offspring1-9. Recent studies in animal models have shown that maternal exercise before and during pregnancy abolishes the age-related development of impaired glucose metabolism10-15, decreased cardiovascular function16 and increased adiposity11,15; however, the underlying mechanisms for maternal exercise to improve offspring's health have not been identified. In the present study, we identify an exercise-induced increase in the oligosaccharide 3'-sialyllactose (3'-SL) in milk in humans and mice, and show that the beneficial effects of maternal exercise on mouse offspring's metabolic health and cardiac function are mediated by 3'-SL. In global 3'-SL knockout mice (3'-SL-/-), maternal exercise training failed to improve offspring metabolic health or cardiac function in mice. There was no beneficial effect of maternal exercise on wild-type offspring who consumed milk from exercise-trained 3'-SL-/- dams, whereas supplementing 3'-SL during lactation to wild-type mice improved metabolic health and cardiac function in offspring during adulthood. Importantly, supplementation of 3'-SL negated the detrimental effects of a high-fat diet on body composition and metabolism. The present study reveals a critical role for the oligosaccharide 3'-SL in milk to mediate the effects of maternal exercise on offspring's health. 3'-SL supplementation is a potential therapeutic approach to combat the development of obesity, type 2 diabetes and cardiovascular disease.

Effects of Exercise to Improve Cardiovascular Health.

Obesity is a complex disease that affects whole body metabolism and is associated with an increased risk of cardiovascular disease (CVD) and Type 2 diabetes (T2D). Physical exercise results in numerous health benefits and is an important tool to combat obesity and its co-morbidities, including cardiovascular disease. Exercise prevents both the onset and development of cardiovascular disease and is an important therapeutic tool to improve outcomes for patients with cardiovascular disease. Some benefits of exercise include enhanced mitochondrial function, restoration and improvement of vasculature, and the release of myokines from skeletal muscle that preserve or augment cardiovascular function. In this review we will discuss the mechanisms through which exercise promotes cardiovascular health.