Aerobic interval training reduces inducible ventricular arrhythmias in diabetic mice after myocardial infarction
- 759 Downloads
Diabetes mellitus (DM) increases the risk of heart failure after myocardial infarction (MI), and aggravates ventricular arrhythmias in heart failure patients. Although exercise training improves cardiac function in heart failure, it is still unclear how it benefits the diabetic heart after MI. To study the effects of aerobic interval training on cardiac function, susceptibility to inducible ventricular arrhythmias and cardiomyocyte calcium handling in DM mice after MI (DM-MI). Male type 2 DM mice (C57BLKS/J Lepr db /Lepr db ) underwent MI or sham surgery. One group of DM-MI mice was submitted to aerobic interval training running sessions during 6 weeks. Cardiac function and structure were assessed by echocardiography and magnetic resonance imaging, respectively. Ventricular arrhythmias were induced by high-frequency cardiac pacing in vivo. Protein expression was measured by Western blot. DM-MI mice displayed increased susceptibility for inducible ventricular arrhythmias and impaired diastolic function when compared to wild type-MI, which was associated with disruption of cardiomyocyte calcium handling and increased calcium leak from the sarcoplasmic reticulum. High-intensity exercise recovered cardiomyocyte function in vitro, reduced sarcoplasmic reticulum diastolic calcium leak and significantly reduced the incidence of inducible ventricular arrhythmias in vivo in DM-MI mice. Exercise training also normalized the expression profile of key proteins involved in cardiomyocyte calcium handling, suggesting a potential molecular mechanism for the benefits of exercise in DM-MI mice. High-intensity aerobic exercise training recovers cardiomyocyte function and reduces inducible ventricular arrhythmias in infarcted diabetic mice.
KeywordsDiabetes mellitus Myocardial infarction Arrhythmias Calcium Aerobic interval training
We thank R. Røsbjørgen for technical assistance, J. Nauman for statistical support, and G. J. J. Silva, and J. B. N. Moreira for very helpful advices. This study was funded by K.G. Jebsen Foundation, The Norwegian Council on Cardiovascular Disease, The Research Council of Norway and Liaison Committee between the Central Norway Regional Health Authority (RHA), the Norwegian University of Science and Technology (NTNU), and the European Commission (FP7-Health-2013; OPTIMEX-602405).
Conflict of interest
On behalf of all the authors, the corresponding author states that there is no conflict of interest.
- 12.Fein F, Scheuer J (1990) Heart disease in diabetes mellitus: theory and practice. In: Porte DJ (ed) Rifkin H. Elsevier, New York, pp 812–823Google Scholar
- 15.Hollekim-Strand SM, Bjorgaas MR, Albrektsen G, Tjonna AE, Wisloff U, Ingul CB (2014) High-intensity interval exercise effectively improves cardiac function in patients with type 2 diabetes mellitus and diastolic dysfunction: a randomized controlled trial. J Am Coll Cardiol 64:1758–1760. doi: 10.1016/j.jacc.2014.07.971 PubMedCrossRefGoogle Scholar
- 17.Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J (1998) Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care 21:69–75. doi: 10.2337/diacare.21.1.69 PubMedCrossRefGoogle Scholar
- 18.Milberg P, Pott C, Frommeyer G, Fink M, Ruhe M, Matsuda T, Baba A, Klocke R, Quang TH, Nikol S, Stypmann J, Osada N, Muller FU, Breithardt G, Noble D, Eckardt L (2012) Acute inhibition of the Na(+)/Ca(2+) exchanger reduces proarrhythmia in an experimental model of chronic heart failure. Heart Rhythm 9:570–578. doi: 10.1016/j.hrthm.2011.11.004 PubMedCrossRefGoogle Scholar
- 19.Oort RJv, McCauley MD, Dixit SS, Pereira L, Yang Y, Respress JL, Wang Q, Almeida ACD, Skapura DG, Anderson ME, Bers DM, Wehrens XHT (2010) Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failureclinical perspective. Circulation 122:2669–2679. doi: 10.1161/CIRCULATIONAHA.110.982298 PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Robinson E, Cassidy RS, Tate M, Zhao Y, Lockhart S, Calderwood D, Church R, McGahon MK, Brazil DP, McDermott BJ, Green BD, Grieve DJ (2015) Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. Basic Res Cardiol 110:20. doi: 10.1007/s00395-015-0476-7 PubMedCentralPubMedCrossRefGoogle Scholar
- 26.Stolen TO, Hoydal MA, Kemi OJ, Catalucci D, Ceci M, Aasum E, Larsen T, Rolim N, Condorelli G, Smith GL, Wisloff U (2009) Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy. Circ Res 105:527–536. doi: 10.1161/CIRCRESAHA.109.199810 PubMedCrossRefGoogle Scholar
- 27.Tjønna AE, Lee SJ, Rognmo Ø, Stølen TO, Bye A, Haram PM, Loennechen JP, Al-Share QY, Skogvoll E, Slørdahl SA, Kemi OJ, Najjar SM, Wisløff U (2008) Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome a pilot study. Circulation 118:346–354. doi: 10.1161/CIRCULATIONAHA.108.772822 PubMedCentralPubMedCrossRefGoogle Scholar
- 28.Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt FW, Wijns W, Task Force on the Management of Acute Myocardial Infarction of the European Society of C (2003) Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 24:28–66. doi: 10.1016/S0195-668X(02)00618-8 PubMedGoogle Scholar
- 30.Wisløff U, Støylen A, Loennechen JP, Bruvold M, Rognmo Ø, Haram PM, Tjønna AE, Helgerud J, Slørdahl SA, Lee SJ, Videm V, Bye A, Smith GL, Najjar SM, Ellingsen Ø, Skjærpe T (2007) Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients. Circulation 115:3086–3094. doi: 10.1161/CIRCULATIONAHA.106.675041 PubMedCrossRefGoogle Scholar
- 32.Zethelius B, Gudbjornsdottir S, Eliasson B, Eeg-Olofsson K, Cederholm J, Swedish National Diabetes R (2014) Level of physical activity associated with risk of cardiovascular diseases and mortality in patients with type-2 diabetes: report from the Swedish National Diabetes Register. Eur J Prev Cardiol 21:244–251. doi: 10.1177/2047487313510893 PubMedCrossRefGoogle Scholar