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.

Exposure of neonatal rats to maternal cafeteria feeding during suckling alters hepatic gene expression and DNA methylation in the insulin signalling pathway

“…This would provide a means of alternative disposal in glucose adipose tissue rather than liver. Sex differences in phenotypic outcomes of Irs2 (Masaki et al 2004) and PPARg knockout (Duan et al 2010;Kadowaki et al 2007) and Akt1 activation (Foryst-Ludwig et al 2011;Chen et al 2013) have been reported previously.…”

Gender Differences in Ventricular Remodeling and Function in College Athletes, Insights from Lean Body Mass Scaling and Deformation Imaging

“…This would, however, be consistent with animal models demonstrating that females have higher LV hypertrophic response to exercise compare to males when compared for quantity of exercise. 24 With regards to our secondary objectives, the small differences in LVEF or LVGLS did not translate in meaningful differences in stroke volume index or the more load independent metrics of ventricular function such as LV strain rate. 25 With regards to atrial function metrics, our study also suggests absence of meaningful sex related differences.…”

Sex and Sex Hormone–Dependent Cardiovascular Stress Responses

“…5 We demonstrated recently that female hearts after chronic exercise with forced treadmill running showed augmented Akt phosphorylation compared with male hearts, indicating activation of this pathway. 6 Taken together, it appears that female hearts have a stronger capability to adapt to a protective exercise-induced MH phenotype.…”

“…5,6 The underlying molecular mechanisms of these sex differences in exerciseinduced MH are multifactorial. Konhilas et al 5 investigated multiple signaling molecules involved in the development of MH including enhanced proportional increase of Ca 2+ /calmodulin-dependent kinase (CaMK) activity in trained female hearts compared with males and a persistent phosphorylation of glycogen synthase kinase 3 beta (GSK-3β).…”

“…10 Along this line, enhanced training-induced hypertrophic response in female mice is associated with augmented adipose tissue lipolysis, increased plasma FFA levels, induction of cardiac genes involved in fatty acid uptake and oxidation (eg, CD36, carnitine palmitoyltransferase 1β, and peroxisome proliferator-activated receptor-α), and a reduced rate of glucose uptake measured by [ 18 F]-2-fluorodeoxyglucose uptake with positron emission tomography. 6 Figure 1). Following this concept, peripheral fat seems to be target (eg, sympathetic stimuli) and mediator (eg, FFA release and aromatase-dependent hormone release) during the development of physiological MH.…”