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(Circulation Research. 2009;105:527.)
© 2009 American Heart Association, Inc.

Cellular Biology

Interval Training Normalizes Cardiomyocyte Function, Diastolic Ca²⁺ Control, and SR Ca²⁺ Release Synchronicity in a Mouse Model of Diabetic Cardiomyopathy

Tomas O. Stølen, Morten Andre Høydal, Ole Johan Kemi, Daniele Catalucci, Marcello Ceci, Ellen Aasum, Terje Larsen, Natale Rolim, Gianluigi Condorelli, Godfrey L. Smith, Ulrik Wisløff

From the Department of Circulation and Medical Imaging (T.O.S., M.A.H., N.R., G.L.S., U.W.), Norwegian University of Science and Technology, Trondheim, Norway; St Olavs University Hospital (T.O.S., M.A.H., U.W.), Trondheim, Norway; the Institute of Biomedical and Life Sciences (O.J.K., G.L.S.), University of Glasgow, UK; the Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica (D.C., M.C., G.C.), Scientific and Technology Pole, Milan, Italy; the Istituto Tecnologie Biomediche (ITB) - Consiglio Nazionale delle Ricerche (CNR) (D.C.), Segrate, Milan, Italy; the Department of Medical Physiology (E.A., T.L.), University of Tromsø, Norway; EBRI, European Brain Research Institute-Rita Levi Foundation, via Del Fosso di Fiorano Rome; and the Division of Cardiology, Department of Medicine (G.C.), University of California San Diego, La Jolla.

Correspondence to Ulrik Wisløff, Norwegian University of Science and Technology, Department of Circulation and Medical Imaging, Olav Kyrres gt. 9, 7489 Trondheim, Norway. E-mail ulrik.wisloff{at}ntnu.no

Rationale: In the present study we explored the mechanisms behind excitation–contraction (EC) coupling defects in cardiomyocytes from mice with type-2 diabetes (db/db).

Objective: We determined whether 13 weeks of aerobic interval training could restore cardiomyocyte Ca²⁺ cycling and EC coupling.

Methods and Results: Reduced contractility in cardiomyocytes isolated from sedentary db/db was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca²⁺ leak, reduced synchrony of Ca²⁺ release, reduced transverse (T)-tubule density, and lower peak systolic and diastolic Ca²⁺ and caffeine-induced Ca²⁺ release. Additionally, the rate of SR Ca²⁺ ATPase–mediated Ca²⁺ uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca²⁺ release indicated increased Na⁺/Ca²⁺-exchanger activity. The increased SR-Ca²⁺ leak was attributed to increased Ca²⁺-calmodulin–dependent protein kinase (CaMKII) phosphorylation, supported by the normalization of SR-Ca²⁺ leak on inhibition of CaMKII (AIP). Exercise training restored contractile function associated with restored SR Ca²⁺ release synchronicity, T-tubule density, twitch Ca²⁺ amplitude, SR Ca²⁺ ATPase and Na⁺/Ca²⁺-exchanger activities, and SR-Ca²⁺ leak. The latter was associated with reduced phosphorylation of cytosolic CaMKII. Despite normal contractile function and Ca²⁺ handling after the training period, phospholamban was hyperphosphorylated at Serine-16. Protein kinase A inhibition (H-89) in cardiomyocytes from the exercised db/db group abolished the differences in SR-Ca²⁺ load when compared with the sedentary db/db mice. EC coupling changes were observed without changes in serum insulin or glucose levels, suggesting that the exercise training–induced effects are not via normalization of the diabetic condition.

Conclusions: These data demonstrate that aerobic interval training almost completely restored the contractile function of the diabetic cardiomyocyte to levels close to sedentary wild type.

Key Words: diabetes mellitus • exercise training • Ca²⁺-calmodulin–dependent protein kinase • ryanodine receptor and calcium handling