Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlar...Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.展开更多
Background Obesity is a risk factor for developing cardiometabolic disease.Exercise training is pivotal in the treatment of obesity and is associated with reduced cardiovascular mortality.This study examined the effec...Background Obesity is a risk factor for developing cardiometabolic disease.Exercise training is pivotal in the treatment of obesity and is associated with reduced cardiovascular mortality.This study examined the effect of high-fat feeding on cardiac morphology and mitochondrial function,alongside the mitigating effects of voluntary exercise training.Methods Six-week-old male C57Bl/6 J mice commenced a high fat diet(HFD)or chow diet and were randomized to receive locked(sedentary)or unlocked(voluntary exercise training(VET))running wheels at 10 weeks of age.Mice were monitored until 30 weeks of age and euthanized for collection of tissues.Magnetic resonance imaging was performed to assess body composition,and echocardiography was performed to assess cardiac function.Results Compared with chow-fed animals,the HFD increased body weight and adiposity and decreased cardiolipins(CL)in the heart,which are required for maintaining adequate mitochondrial respiration.Importantly,VET reversed these effects and induced physiological cardiac hypertrophy.Cardiac mitochondrial respiratory chain analysis revealed decreased complexes II and IV activity following high fat feeding,while VET enhanced complex I activity,emphasizing the cardioprotective effect of exercise training in obesity.Conclusion This study uncovers mechanisms by which obesity and exercise impact cardiac mitochondrial health and suggests the mitochondria is a therapeutic target in obesity-related cardiovascular diseases.展开更多
基金supported by grants from NHMRC(Grant No.1125514 and 2029334 to JRM,and 1120129 to JRM and CEH)National Heart Foundation of Australia(Vanguard-105720)+6 种基金the Victorian Government’s Operational Infrastructure Support Programsupported by a joint Baker Heart and Diabetes Institute-La Trobe University doctoral scholarshipsupported by Future Leader Fellowships from the National Heart Foundation of Australia(Grant No.102536 to EJH,102539 to KLW,and 102206 to ALG)supported by an Alice Baker and Eleanor Shaw Fellowship(The Baker Foundation,Australia)supported by a NHMRC Senior Research(Grant No.1078985)Baker Fellowship(The Baker Foundation,Australia)Cardiovascular Research Capacity Program-Research Leadership GrantsCardiovascular Research Capacity Program-Research Leadership Grants(NSW Health)。
文摘Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.
基金MAF is supported by an NHMRC Investigator Grant(APP1194141)Research in his laboratory was supported by project grants from the NHMRC(APP1042465,APP1041760,and APP1156511).
文摘Background Obesity is a risk factor for developing cardiometabolic disease.Exercise training is pivotal in the treatment of obesity and is associated with reduced cardiovascular mortality.This study examined the effect of high-fat feeding on cardiac morphology and mitochondrial function,alongside the mitigating effects of voluntary exercise training.Methods Six-week-old male C57Bl/6 J mice commenced a high fat diet(HFD)or chow diet and were randomized to receive locked(sedentary)or unlocked(voluntary exercise training(VET))running wheels at 10 weeks of age.Mice were monitored until 30 weeks of age and euthanized for collection of tissues.Magnetic resonance imaging was performed to assess body composition,and echocardiography was performed to assess cardiac function.Results Compared with chow-fed animals,the HFD increased body weight and adiposity and decreased cardiolipins(CL)in the heart,which are required for maintaining adequate mitochondrial respiration.Importantly,VET reversed these effects and induced physiological cardiac hypertrophy.Cardiac mitochondrial respiratory chain analysis revealed decreased complexes II and IV activity following high fat feeding,while VET enhanced complex I activity,emphasizing the cardioprotective effect of exercise training in obesity.Conclusion This study uncovers mechanisms by which obesity and exercise impact cardiac mitochondrial health and suggests the mitochondria is a therapeutic target in obesity-related cardiovascular diseases.
