Interval training normalizes cardiomyocyte function, diastolic Ca 2+ 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

Research output: Contribution to journalArticlepeer-review

Abstract

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-Ca 2+ leak was attributed to increased Ca2+-calmodulin- dependent protein kinase (CaMKIIS) phosphorylation, supported by the normalization of SR-Ca2+ leak on inhibition of CaMKIIS (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 CaMKIIS. 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.

Original languageEnglish
Pages (from-to)527-536
Number of pages10
JournalCirculation Research
Volume105
Issue number6
DOIs
Publication statusPublished - 2009

Keywords

  • Ca-calmodulin-dependent protein kinase
  • Diabetes mellitus
  • Exercise training
  • Ryanodine receptor and calcium handling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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