Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin-6 Receptor–Dependent Mechanism

HomeCirculationVol. 140, No. 20Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin-6 Receptor–Dependent Mechanism Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBAerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin-6 Receptor–Dependent MechanismCardiac Analysis of a Double-Blind Randomized Controlled Clinical Trial in Abdominally Obese Humans Regitse Højgaard Christensen, MD, PhD, Louise Lang Lehrskov, MD, PhD, Anne-Sophie Wedell-Neergaard, MD, PhD, Grit Elster Legaard, MD, Mathias Ried-Larsen, PhD, Kristian Karstoft, MD, PhD, Rikke Krogh-Madsen, MD, PhD, Bente Klarlund Pedersen, MD, DMSc, Helga Ellingsgaard, PhD and Jaya Birgitte Rosenmeier, MD, PhD Regitse Højgaard ChristensenRegitse Højgaard Christensen Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Louise Lang LehrskovLouise Lang Lehrskov Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Anne-Sophie Wedell-NeergaardAnne-Sophie Wedell-Neergaard Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Grit Elster LegaardGrit Elster Legaard Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Mathias Ried-LarsenMathias Ried-Larsen Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Kristian KarstoftKristian Karstoft Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Rikke Krogh-MadsenRikke Krogh-Madsen Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Bente Klarlund PedersenBente Klarlund Pedersen Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). , Helga EllingsgaardHelga Ellingsgaard Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark (R.H.C., L.L.L., A.-S.W.-N., G.E.L., M.R.-L., K.K., R.K.-M., B.K.P., H.E.). and Jaya Birgitte RosenmeierJaya Birgitte Rosenmeier Jaya Birgitte Rosenmeier, MD, PhD, Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark. Email E-mail Address: [email protected] Department of Cardiology, Copenhagen University Hospital Bispebjerg, Denmark (J.B.R.). Originally published11 Nov 2019https://doi.org/10.1161/CIRCULATIONAHA.119.042287Circulation. 2019;140:1684–1686Epicardial and pericardial adipose tissues (EAT and PAT) are cardiac fat depots and independent risk factors of cardiovascular disease. Exercise training reduces EAT and PAT1 through lipolysis, which is partially induced by acute discharge of adrenaline2 and interleukin-6 (IL-6).3 IL-6 has been shown to stimulate myocardial hypertrophy in vitro and in vivo,4 but it is not known whether IL-6 regulates exercise-induced adaptations in cardiac fat and left myocardial mass (LVM) in humans. Thus, the present study aimed to test whether aerobic exercise training reduces cardiac fat through an IL-6 receptor–dependent mechanism and moreover to investigate the role of IL-6 signaling in training-induced adaptations of the myocardium.This study presents the preplanned secondary analysis of a larger single-center, double-blind, randomized exercise intervention study. The methods for this study have been described previously.1,5 In short, the final study population comprised 52 abdominally obese but otherwise healthy participants randomly assigned to moderate/high-intensity aerobic exercise (3 sessions of 45 minutes per week reaching 70%–85% of Vo2max) or no exercise with or without monthly infusions of the IL-6 receptor antagonist tocilizumab (RoActemra, Roche Pharma AG) in the clinical standard dose of 8 mg/kg or saline (placebo; Figure, A).Download figureDownload PowerPointFigure. Effects of interleukin-6 (IL-6) receptor (IL-6R) blockade and exercise on cardiac fat and function. Study design (A), epicardial fat mass changes (B), pericardial fat mass changes (C), left ventricular mass (LVM) changes (D), stroke volume changes (E), and end-diastolic volume (left ventricular ejection fraction [LVEF]) changes (F) in response to a 12-week exercise training intervention with and without IL-6R blockade (tocilizumab). B, *P=0.006, #P=0.002. C, *P=0.004. D, *P<0.001, #P=0.029.Anthropometric measures, biochemistry, diet, and free-living physical activity were monitored.5EAT, PAT, myocardial mass, and hemodynamic variables were recorded with a magnetic resonance scanner (1.5 T, Philips) using standard cardiac projections as described previously.1 Cardiovascular imaging software (Cvi42, version 5.2) was applied to calculate cardiac function, muscle, and fat mass.1Baseline characteristics were evaluated by ANOVA/Kruskal Wallis/χ2 test as appropriate. ANCOVA was performed on intervention-induced changes with the baseline value used as the covariate, and group means were adjusted for baseline (least squares mean). Group contrasts were obtained with the Student t test. In a subanalysis, the interaction of tocilizumab (yes/no) and exercise (yes/no) was investigated by ANCOVA.Baseline characteristics, including mean±SD age (44±12 years), sex (21% men), body weight (95±16 kg), and body mass index (33±5 kg/m2), did not differ between groups (P=0.38, P=0.64, P=0.78, P=0.99), nor did free-living physical activity (all P>0.29) or caloric intake (P=0.57).EAT mass was reduced by 8 g (95% CI, 2–14, P=0.006; ≈58% [95% CI, 20–96], P=0.004) more in the exercise+placebo group compared with the no exercise+placebo group (Figure, B). The exercise-induced reduction in EAT was greatly diminished in the exercise+tocilizumab group (2 g [95% CI, −2 to 6]; ≈11% [95% CI, −16 to 38]), and consequently, EAT mass was reduced by 9 g (95% CI, 4–15, P=0.002; ≈46% [95% CI, 9–83], P=0.016) more in the exercise+placebo group compared with the exercise+tocilizumab group (Figure [B]). Mirroring this, an interaction subanalysis revealed that tocilizumab diminished the effect of exercise on EAT mass (P=0.027).Although not significant, total body weight showed similar tendencies and was reduced by 1.5 kg (95% CI, −0.2 to 3.2; P=0.079) more in the exercise+placebo group compared with the exercise+tocilizumab group. The same was the case with PAT mass (11 g [95% CI, −15 to 37], P=0.41; ≈17% [95% CI, 0–34], P=0.049) for exercise+placebo versus exercise+tocilizumab, respectively (Figure, C).PAT was increased in the no exercise+tocilizumab group (28 g [95% CI, 9–47]; ≈22% [95% CI, 9–34]) but not in the no exercise+placebo group (−12 g [95% CI, −31 to 7] or 0% [95% CI, −13 to 12]), rendering a difference in PAT between these groups of 40 g (95% CI, 13–67, P=0.004; ≈22% [95% CI, 4–40], P=0.017]).LVM increased by 20 g (95% CI, 10–31, P=0.0003; ≈16% [95% CI, 8–25], P=0.0002) more in the exercise+placebo group compared with the no exercise+placebo group.The effect of exercise was abolished with tocilizumab, thus increasing LVM by 12 g (95% CI, 1–22, p=0.029; ≈10% [95% CI, 2–18], P=0.019) more in the exercise+placebo group than the exercise+tocilizumab group (Figure, D). Although not significant, this corresponded to stroke volume and end-diastolic volume, which showed changes similar to that for LVM (Figure, E and F), whereas left ventricular ejection fraction (P=0.19) and heart rate (P=0.34) remained unchanged across the 4 groups.There was no difference in acute catecholamine discharge between the exercise groups, as reported previously.5This study tested whether administration of the IL-6 receptor antagonist alters the change in EAT, PAT, and LVM after a 12-week exercise intervention in sedentary obese individuals. This is the first study to demonstrate that IL-6 receptor activation is required for aerobic exercise training to reduce EAT and prevent PAT accumulation. We also show that IL-6 plays a critical role for exercise-induced increases in LVM that are independent of acute discharges in catecholamines, diet, or free-living physical activity.EAT was more responsive to training than was PAT, which speculatively could be caused by a higher IL-6 receptor expression, although the small study size cannot be excluded.IL-6 receptor signaling has previously been associated with pathophysiological cardiac hypertrophy, but here we demonstrate that IL-6 signaling is also involved in exercise-induced hypertrophic and fat-reducing effects of the heart.Sources of FundingThis study was funded by TrygFonden. The Centre for Physical Activity Research is supported by a grant from TrygFonden, and the Centre of Inflammation and Metabolism is a member of DD2, the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grants 09-067009 and 09-075724). Dr Christensen’s salary was financed by a grant from the Danish Heart foundation (16-R107-A6704-22970). Dr Lehrskov’s salary was partly financed by a grant from the Danish Diabetes Academy, which is supported by the Novo Nordisk Foundation. Running costs were financially supported by an Aase and Ejnar Danielsen grant (10-001271).DisclosuresNone.FootnotesData sharing: Data are not available online. The data that support the findings of this study are available from the first author ([email protected]com) on reasonable request.https://www.ahajournals.org/journal/circJaya Birgitte Rosenmeier, MD, PhD, Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark. Email [email protected]dkReferences1. Christensen RH, Wedell-Neergaard AS, Lehrskov LL, Legaard GE, Dorph EB, Larsen MK, Laubo N, Fagerlind SR, Seide SK, Nymand S, et al. 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November 12, 2019Vol 140, Issue 20 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.042287PMID: 31710522 Originally publishedNovember 11, 2019 Keywordsadipose tissuereceptors, interleukin-6PDF download Advertisement SubjectsLipids and CholesterolMetabolismMyocardial BiologyTranslational Studies