Abstract 3506: Calcium Leak and Contractility in Diabetic Cardiomyocytes are Normalized after Exercise Training
Introduction: Patients with type 2 diabetes has increased risk for lethal arrhythmias and sudden cardiac death. Recently, diastolic SR Ca2+ leak has been linked to delayed afterdepolarisation and arrhythmias. This increased SR Ca2+ leak is demonstrated in db/db mice along side with increased risk of arrhythmia during ischemia-reperfusion.
Method: Cardiomyocytes from high intensity aerobic interval trained (AIT) db/db mice, sedentary db/db mice and to wild type mice (WT) were isolated for measuring Ca2+ handling and fractional shortening (FS), by epifluorecense, and confocal microscopy.
Results: VO2max in AIT db/db increased more than 13% above the level of db/db sedentary and WT. The hypertrophied myocytes in the db/db decreased by 27% (P<0.01) after AIT and were similar to WT. FS in db/db increased after AIT (from 3.5±1.6% to 7.8±1.4%, P<0.02) and were similar to WT. AIT improved diastolic function (time to relengthening) (P<0.01) alongside with increased Ca2+ decay (P<0.01) and were similar to WT. Normalised SR Ca2+ leak decreased from 13±3% to 3±4% after AIT (P<0.01) and were similar to WT. Ca2+ wave frequency were reduced by 74% (P<0.05) after AIT. NCX function was increased in db/db sedentary (P<0.05), while AIT reduced NCX function to WT levels. SR Ca2+ leak were normalized in the db/db sedentary when inhibiting CaMKII (P<0.01), but not after PKA inhibition. This was also confirmed by Western Blots, showing increased phosphorylated CaMKII in db/db sedentary (P<0.05) and reduced phosphorylated CaMKII to WT levels after AIT. Both Ca2+ release synchrony and to T-tubule density, which is closely related, were reduced in sedentary db/db (P<0.05 and P<0.01, respectively) and restored to WT levels after AIT.
Conclusion: PKA phosphorylation after AIT appears as an important mechanism behind improvements in intracellular Ca2+ cycling and SR Ca2+ loading in the db/db mice, whereas CaMKII appears more important than PKA for the control of RyR2 sensitivity and SR Ca2+ leak. This taken together with restored T-tubule density and Ca2+ release synchrony, AIT restored FS in db/db mice.