title: Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy.
abstract: BACKGROUND
  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 Ca(2+) cycling and EC coupling.
  
  
  RESULTS
  Reduced contractility in cardiomyocytes isolated from sedentary db/db was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca(2+) leak, reduced synchrony of Ca(2+) release, reduced transverse (T)-tubule density, and lower peak systolic and diastolic Ca(2+) and caffeine-induced Ca(2+) release. Additionally, the rate of SR Ca(2+) ATPase-mediated Ca(2+) uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca(2+) release indicated increased Na(+)/Ca(2+)-exchanger activity. The increased SR-Ca(2+) leak was attributed to increased Ca(2+)-calmodulin-dependent protein kinase (CaMKIIdelta) phosphorylation, supported by the normalization of SR-Ca(2+) leak on inhibition of CaMKIIdelta (AIP). Exercise training restored contractile function associated with restored SR Ca(2+) release synchronicity, T-tubule density, twitch Ca(2+) amplitude, SR Ca(2+) ATPase and Na(+)/Ca(2+)-exchanger activities, and SR-Ca(2+) leak. The latter was associated with reduced phosphorylation of cytosolic CaMKIIdelta. Despite normal contractile function and Ca(2+) 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-Ca(2+) 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.
authors.affiliation: Norwegian University of Science and Technology, Department of Circulation and Medical Imaging, Olav Kyrres gt. 9, 7489 Trondheim, Norway.
authors.forename: Tomas O
authors.initials: TO
authors.lastname: Stølen
authors.forename: Morten Andre
authors.initials: MA
authors.lastname: Høydal
authors.forename: Ole Johan
authors.initials: OJ
authors.lastname: Kemi
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceci
authors.forename: Ellen
authors.initials: E
authors.lastname: Aasum
authors.forename: Terje
authors.initials: T
authors.lastname: Larsen
authors.forename: Natale
authors.initials: N
authors.lastname: Rolim
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Ulrik
authors.initials: U
authors.lastname: Wisløff
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003971:Diastole; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D002118:Calcium