title: Sex differences in physiological cardiac hypertrophy are associated with exercise-mediated changes in energy substrate availability.
abstract: Exercise-induced cardiac hypertrophy has been recently identified to be regulated in a sex-specific manner. In parallel, women exhibit enhanced exercise-mediated lipolysis compared with men, which might be linked to cardiac responses. The aim of the present study was to assess if previously reported sex-dependent differences in the cardiac hypertrophic response during exercise are associated with differences in cardiac energy substrate availability/utilization. Female and male C57BL/6J mice were challenged with active treadmill running for 1.5 h/day (0.25 m/s) over 4 wk. Mice underwent cardiac and metabolic phenotyping including echocardiography, small-animal PET, peri-exercise indirect calorimetry, and analysis of adipose tissue (AT) lipolysis and cardiac gene expression. Female mice exhibited increased cardiac hypertrophic responses to exercise compared with male mice, measured by echocardiography [percent increase in left ventricular mass (LVM): female: 22.2 ± 0.8%, male: 9.0 ± 0.2%; P < 0.05]. This was associated with increased plasma free fatty acid (FFA) levels and augmented AT lipolysis in female mice after training, whereas FFA levels from male mice decreased. The respiratory quotient during exercise was significantly lower in female mice indicative for preferential utilization of fatty acids. In parallel, myocardial glucose uptake was reduced in female mice after exercise, analyzed by PET {injection dose (ID)/LVM [%ID/g]: 36.8 ± 3.5 female sedentary vs. 28.3 ± 4.3 female training; P < 0.05}, whereas cardiac glucose uptake was unaltered after exercise in male counterparts. Cardiac genes involved in fatty acid uptake/oxidation in females were increased compared with male mice. Collectively, our data demonstrate that sex differences in exercise-induced cardiac hypertrophy are associated with changes in cardiac substrate availability and utilization.
authors.affiliation: Center for Cardiovascular Research (CCR Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Foryst-Ludwig
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kreissl
authors.forename: Christiane
authors.initials: C
authors.lastname: Sprang
authors.forename: Beata
authors.initials: B
authors.lastname: Thalke
authors.forename: Christian
authors.initials: C
authors.lastname: Böhm
authors.forename: Verena
authors.initials: V
authors.lastname: Benz
authors.forename: Dennis
authors.initials: D
authors.lastname: Gürgen
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.forename: Carola
authors.initials: C
authors.lastname: Schubert
authors.forename: Knut
authors.initials: K
authors.lastname: Mai
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
authors.forename: Joachim
authors.initials: J
authors.lastname: Spranger
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002151:Calorimetry; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000503:physiopathology*; D004452:Echocardiography; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000503:physiopathology; D019344:Lactic Acid / Q000378:metabolism; D008066:Lipolysis / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D049268:Positron-Emission Tomography; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D019275:Radiopharmaceuticals; D012420:Running / Q000502:physiology; D012727:Sex Characteristics
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D019344:Lactic Acid; D012313:RNA; D006003:Glycogen; D005947:Glucose