The role of GSK3beta in regulating murine cardiac SERCA function in male and female mice.

Abstract

Cardiac contractile function is largely regulated by calcium (Ca2+) cycling within cardiomyocytes. The sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2) catalyzes the active transport of Ca2+ into the sarcoplasmic reticulum thereby influencing cardiac diastole and free intracellular Ca2+ levels. Phospholamban is an inhibitor of SERCA2, and together, both are paramount to cardiac Ca2+ regulation. It is well established that SERCA2 dysfunction pathologically contributes to cardiomyopathy and heart failure. My previous work showed that inhibiting the enzyme glycogen synthase kinase-3 (GSK3) with a sub-therapeutic dose of lithium chloride (LiCl, 10 mg/kg/day – 0.02 mmol/L [serum]), improves cardiac SERCA function by increasing the ratio of SERCA2:PLN in male C57BL/6J mice. However, it is unclear whether this effect can be reproduced in other models or affects overall cardiac function and morphology. Therefore, in this thesis, I investigated whether the improvements observed previously with sub-therapeutic LiCl on cardiac SERCA function could affect cardiac systolic and diastolic function in male WT mice (data chapter 1), whether sub-therapeutic LiCl affected SERCA susceptibility to thermal inactivation (data chapter 2), if sub-therapeutic LiCl showed similar improvements to cardiac SERCA function in female WT mice, and whether this effect was translated to the ovariectomized (OVX) female mouse model of menopause (data chapter 3). In the final data chapter (data chapter 4), I examined whether GSK3β-specific inhibition can benefit cardiac SERCA function, contractility and morphology in the D2-mdx mouse, a preclinical model of Duchenne muscular dystrophy. In data chapter 1, I found that LiCl induces an eccentric hypertrophy, independent of changes to SERAC function. Data chapter 2 shows a preservative effect of LiCl treatment on SERCA during thermal inactivation. Data chapter 3 indicated a similar effect on SERCA function in females as shown previously in males, however this effect was less effective in OVX females. Finally, data from Chapter 4 showed that GSK3β-specific inhibition in D2-mdx mice preserved diastolic function; however, this was not due to changes in cardiac SERCA function. Together, these studies present the therapeutic value of GSK3 inhibition in physiological and pathological states of the heart, though this may not entirely be dependent on improvements to SERCA function.