Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation

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Abstract
The present study was undertaken to assess the effects of exercise training (ExT) initiated after the onset of diabetes on cardiac ryanodine receptor expression and function. Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin (STZ). Three weeks after STZ injection, diabetic rats were divided into two groups. One group underwent ExT for 4 wk while the other group remained sedentary. After 7 wk of sedentary diabetes, cardiac fractional shortening, rate of rise of left ventricular pressure, and myocyte contractile velocity were reduced by 14, 36, 44%, respectively. Spontaneous Ca2+ spark frequency increased threefold, and evoked Ca2+ release was dyssynchronous with diastolic Ca2+ releases. Steady-state type 2 ryanodine receptor (RyR2) protein did not change, but its response to Ca2+ was altered. RyR2 also exhibited 1.8- and 1.5-fold increases in phosphorylation at Ser2808 and Ser2814. PKA activity was reduced by 75%, but CaMKII activity was increased by 50%. Four weeks of ExT initiated 3 wk after the onset of diabetes blunted decreases in cardiac fractional shortening and rate of left ventricular pressure development, increased the responsiveness of the myocardium to isoproterenol stimulation, attenuated the increase in Ca2+ spark frequency, and minimized dyssynchronous and diastolic Ca2+ releases. ExT also normalized the responsiveness of RyR2 to Ca2+ activation, attenuated increases in RyR2 phosphorylation at Ser2808 and Ser2814, and normalized CaMKII and PKA activities. These data are the first to show that ExT during diabetes normalizes RyR2 function and Ca2+ release from the sarcoplasmic reticulum, providing insights into mechanisms by which ExT during diabetes improves cardiac function.