Where opportunity meets preparation: the crosstalk of microtubules and kinases in hypertrophic cardiomyopathy

Microtubules (MTs), which, together with their post-translationally modified (PTM) forms detyrosination and acetylation are increased in hypertrophic cardiomyopathy (HCM) and heart failure (HF) and have become a promising therapeutic target. Their targeting potential has given rise to developing gene therapy and/or small molecule inhibitors targeting the non-sarcomeric cytoskeleton. Studies employing animal and stem cell models utilize compounds that inhibit MT detyrosination, increase MT acetylation and/or turn to overexpressing the MT tyrosinating enzyme tubulin tyrosine ligase to show their effects on cardiac function and cardiomyocyte contractility. Such approaches corroborate that MT detyrosination and, though demonstrated to a lesser extent, acetylation impair cardiomyocyte contractility. We, therefore, hypothesized whether in HCM, too, the genotype-specific altered MT code underlies diastolic dysfunction and impaired cardiomyocyte relaxation. Our group previously employed our Mybpc3 mouse model and provided evidence that the inhibition of MT detyrosination improves impaired relaxation in HCM. In this thesis, I focused on which signaling pathways underlie an altered MT code in human HCM and how altered kinase signaling could serve as a precursor to impaired relaxation as well as an altered MT code. As outlined in Chapter 1, HCM cardiomyocytes are subject to a multitude of dysregulated processes, including signaling cascades associated with MTs, that are not well-studied. We reasoned that several kinases modulate the contractility of healthy and/or diseased cardiomyocytes, potentially by altering MTs. To dissect the role of MT alterations in cardiac (patho)physiology, we performed studies to define the MT code in different HF models and at different disease stages, and studied which signaling pathways may underlie the altered MT code in human HCM.