Project ID CM-HD2023_21

ThemeCM-HD

Co Supervisor 1A Randall Centre/Basic and Medical Biosciences/FoLSMWebsite

Co Supervisor 1B Muscle Biology/School of Cardiovascular Medicine and Sciences/FoLSMWebsite

Impaired myosin-based regulation as the functional basis for Hypertrophic Cardiomyopathy

Mutations in the genes encoding for cardiac myosin and associated proteins are the most common case of inheritable hypertrophic cardiomyopathy (HCM) a disease with a world-wide incidence of 1:500. HCM is functionally characterized by an impaired relaxation of the heart muscle and a hypercontractile phenotype on both the cellular and molecular level.

We have previously shown that active shortening of heart muscle cells (as would happen in the ejection phase of the cardiac cycle) deactivates cardiac myosin (called ‘shortening de-activation’; SDA) which likely facilitates relaxation of the heart muscle and allows efficient filling of the ventricles during diastole. We there hypothesized that HCM-associated mutations in cardiac myosin and associated proteins lead to HCM and heart failure via impaired SDA.

In this project we will directly test this hypothesis by studying the functional effects of cardiomyopathy-associated mutations in the cardiac myosin-associated regulatory light chain (RLC) on SDA in both isolated cardiac tissue from animal models and engineered human heart tissue (EHT).

In the first year of the project, we will test for the functional effects of the RLC mutations on cardiac muscle mechanics and energetics using isolated cardiac tissue from animal models. In the second year we will create EHT from isogenic iPSC cell lines carrying the mutations followed by characterization of the tissue using a combination of super-resolution imaging and quantitative PCR, which is followed by the functional analysis of the EHT using state-of-the-art physiological and biophysical measurements in the third year.

One representative publication from each co-supervisor:

• Kampourakis and Irving (2021) Nature Comms, 12, 5272

• Lange et al. (2016) Nature Comms, 7, 12120.