Proteasome Dysfunction in Troponin Related Cardiomyopathies

Abstract

Hypertrophic cardiomyopathy (HCM) is a disease characterized by small to significant increases in calcium sensitivity of force development. Our results suggest that patients with mutations which are associated with large increases in calcium sensitivity of force development show poor prognosis. Investigation of two cardiac troponin T (cTnT) transgenic mice, I79N and F110I, which are associated with HCM using a functional proteomics approach showed that several key proteins which are known to be degraded by the proteasome are altered when compared to wild-type cTnT transgenic mice. Skinned fiber studies from I79N and F110I transgenic mice showed that these mutations both caused similar increases in calcium sensitivity of force development (change in pCa50 = approx. 0.22) when compared to wild-type transgenic mice. The 179N and F110I mice both showed significant decreases in 20S proteasome activities related to wild-type cTnT transgenic mice suggesting that proteasomal dysfunction may be a contributing factor to the pathogenesis of HCM. The levels of polyubiquitinated proteins present in the I79N and F110I were also increased relative to wild-type cTnT transgenic mice. Transgenic mice expressing cTnT I79N or cTnT F110I do not develop significant hypertrophy or ventricular fibrosis even after chronic exercise challenge. This suggests that increased heart size may not the critical factor for causing proteasome dysfunction in some cardiomyopathies. These results suggest that the UPS is an important system involved in the pathogenesis of troponin related HCM which is initially caused by significant increases in calcium sensitivity of force development.