Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation

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 Ca ²⁺ 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.