title: Daily exercise prevents diastolic dysfunction and oxidative stress in a female mouse model of western diet induced obesity by maintaining cardiac heme oxygenase-1 levels.
abstract: OBJECTIVE
  Obesity is a global epidemic with profound cardiovascular disease (CVD) complications. Obese women are particularly vulnerable to CVD, suffering higher rates of CVD compared to non-obese females. Diastolic dysfunction is the earliest manifestation of CVD in obese women but remains poorly understood with no evidence-based therapies. We have shown early diastolic dysfunction in obesity is associated with oxidative stress and myocardial fibrosis. Recent evidence suggests exercise may increase levels of the antioxidant heme oxygenase-1 (HO-1). Accordingly, we hypothesized that diastolic dysfunction in female mice consuming a western diet (WD) could be prevented by daily volitional exercise with reductions in oxidative stress, myocardial fibrosis and maintenance of myocardial HO-1 levels.
  
  
  METHODS
  Four-week-old female C57BL/6J mice were fed a high-fat/high-fructose WD for 16weeks (N=8) alongside control diet fed mice (N=8). A separate cohort of WD fed females was allowed a running wheel for the entire study (N=7). Cardiac function was assessed at 20weeks by high-resolution cardiac magnetic resonance imaging (MRI). Functional assessment was followed by immunohistochemistry, transmission electron microscopy (TEM) and Western blotting to identify pathologic mechanisms and assess HO-1 protein levels.
  
  
  RESULTS
  There was no significant body weight decrease in exercising mice, normalized body weight 14.3g/mm, compared to sedentary mice, normalized body weight 13.6g/mm (p=0.38). Total body fat was also unchanged in exercising, fat mass of 6.6g, compared to sedentary mice, fat mass 7.4g (p=0.55). Exercise prevented diastolic dysfunction with a significant reduction in left ventricular relaxation time to 23.8ms for exercising group compared to 33.0ms in sedentary group (p<0.01). Exercise markedly reduced oxidative stress and myocardial fibrosis with improved mitochondrial architecture. HO-1 protein levels were increased in the hearts of exercising mice compared to sedentary WD fed females.
  
  
  CONCLUSIONS
  This study provides seminal evidence that exercise can prevent diastolic dysfunction in WD-induced obesity in females even without changes in body weight. Furthermore, the reduction in myocardial oxidative stress and fibrosis and improved HO-1 levels in exercising mice suggests a novel mechanism for the antioxidant effect of exercise.
authors.affiliation: Division of Cardiovascular Medicine, Diabetes Cardiovascular Center, University of Missouri Columbia, Columbia, MO, USA; Department of Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bostick
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
authors.forename: William
authors.initials: W
authors.lastname: Durante
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Department of Radiology, University of Missouri, Columbia, MO, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Garro
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA; Biomedical Sciences, University of Missouri, Columbia, MO, USA.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Booth
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA. Electronic address: sowersj@health.missouri.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002940:Circadian Rhythm; D003971:Diastole; D066273:Diet, Western; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal / Q000502:physiology*
chemical_list: D051547:Heme Oxygenase-1
keywords: Diastolic dysfunction; Exercise; Heme oxygenase; Obesity; Oxidative stress