Interval training normalizes cCardiomyocyte function, diastolic Ca²⁺ control, and SR Ca²⁺ release synchronicity in a mouse model of diabetic cardiomyopathy

Stølen, T.O. et al. (2009) Interval training normalizes cCardiomyocyte function, diastolic Ca²⁺ control, and SR Ca²⁺ release synchronicity in a mouse model of diabetic cardiomyopathy. Circulation Research, 105(6), pp. 527-536. (doi: 10.1161/CIRCRESAHA.109.199810)

Abstract

In the present study we explored the mechanisms behind excitation-contraction (EC)-coupling defects in cardiomyocytes from mice with type-2 diabetes (db/db), and determined whether 13-weeks of aerobic interval training could restore cardiomyocyte Ca²⁺ cycling and EC-coupling. 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 (SERCA2a)-mediated Ca²⁺ uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca²⁺ release indicated increased Na⁺/Ca²⁺- exchanger (NCX) activity. The increased SR-Ca²⁺ leak was attributed to increased Ca²⁺-calmodulindependent protein kinase (CaMKIIδ) phosphorylation, supported by the normalization of SR-Ca²⁺ leak upon inhibition of CaMKIIδ (AIP). Exercise training restored contractile function associated with restored SR Ca²⁺ release synchronicity, T-tubule density, twitch Ca²⁺ amplitude, SERCA2a and NCX activities, and SR-Ca²⁺ leak. The latter was associated with reduced phosphorylation of cytosolic CaMKIIδ. Despite normal contractile function and Ca²⁺ handling after the training period, phospholamban was hyperphosphorylated at Serine-16. Protein kinase A (PKA) 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. These data demonstrate that aerobic interval training almost completely restored the contractile function of the diabetic cardiomyocyte to levels close to sedentary wild type (WT).

• Item Type: Articles
• Keywords: Diabetes mellitus; exercise training; Ca[2+]-calmodulin–dependent protein kinase; ryanodine receptor and calcium handling
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Godfrey and Kemi, Dr Ole
• Authors: Stølen, T.O., Høydal, M.A., Kemi, O.J., Catalucci, D., Ceci, M., Aasum, E., Larsen, T., Rolim, N., Condorelli, G., Smith, G.L., and Wisløff, U.
• Subjects: R Medicine > RC Internal medicine; Q Science > QR Microbiology
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences
• Journal Name: Circulation Research
• Publisher: American Heart Association
• ISSN: 0009-7330
• ISSN (Online): 1524-4571
• Copyright Holders: Copyright © 2009 American Heart Association
• First Published: First published in Circulation research 105(6):527-536
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.