095 Characterising the Phenotypic Switch in a Murine Model of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) occurs due to mutations in sarcomeric proteins. At the cellular level, HCM characteristics include increased protein synthesis, increased mitochondrial number, altered cell metabolism and cardiomyocyte disorganisation. HCM has variable phenotypic expression and clinical characteristics often present later in life. Using a murine model of human HCM, we have shown that a mutation in cardiac troponin I (cTnI-G203S) is associated with cytoskeletal disorganisation and a hypermetabolic mitochondrial state. Alterations in metabolic activity precede manifestation of the HCM phenotype. However, little is known about the role of signalling pathways in disease progression. The mTOR signalling pathway is a key regulator of protein synthesis and cell metabolism, and may be involved in the development of HCM. Here we examined myocardial ultrastructure and cardiac mTOR signalling in cTnI-G203S mice. Studies were performed in mice before and after the development of HCM (pre- and post-HCM) using TEM and immunoblot methodologies. Pre-HCM cTnI-G203S hearts demonstrated an increasing trend in total and activated mTOR), and a significant increase in sarcomere area (p<0.001, n=2), versus age-matched wt hearts. Post-HCM cTnI-G203S hearts demonstrated (i) significantly higher total and activated mTOR (ptotal<0.05, n=3; pactivated: p<0.05, n=3), and (ii) a significant decrease in sarcomere area (p<0.001, n=2) versus age-matched wt hearts. We conclude that alterations in the mTOR signalling pathway may be involved in the progression of the HCM phenotype. Myocardial ultrastructure appears to alter as the phenotype develops from a pre- to post-cardiomyopathic state.