Discovery of Distinct Molecular Pathways Affected in Mild and Severe Troponin T‐Related Cardiomyopathies

Abstract

Familial hypertrophic cardiomyopathy (FHC) is a genetic heart disease associated with arrhythmias, heart failure and sudden cardiac death. It is known that FHC is primarily caused by sarcomeric protein mutations; however the molecular mechanisms that lead to impaired cardiac function are not well understood. Troponin T (TnT) mutations are the third most common cause of FHC and cause the greatest portion of FHC deaths. To gain insight into the pathways affected in FHC, hearts from two TnT FHC models (I79N and R278C) were investigated by proteomic and metabolomic analysis. The I79N mutation, like most FHC mutations, increases myofilament calcium (Ca) sensitivity, while R278C does not affect Ca sensitivity and has milder cardiac effects. Of approximately 1200 proteins identified, expression of 53 and 76 proteins was changed in I79N and R278C hearts relative to wild‐type hearts respectively. Three major systems affected were the proteasome, antioxidant systems and metabolic pathways. Further investigation by Western blotting and biological assays revealed impaired proteasome function in I79N hearts, as well as increased oxidative stress, antioxidant expression and antioxidant capacity, suggesting higher stress levels in I79N hearts. The results also suggest that glycolysis and galactose metabolism are accelerated in I79N hearts, while fatty acid metabolism appears to be upregulated in R278C hearts, suggesting different energy substrate utilization in mild and severe TnT‐related FHC. Our data suggest that altered metabolism and proteasome dysfunction are important mechanisms in severe TnT‐related FHC.