Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were (1) several key PQC players were more abundant in HCM compared to controls, (2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, (3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, (4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and (5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.

Additional Metadata
Persistent URL dx.doi.org/10.3390/cells8070741, hdl.handle.net/1765/119476
Journal Cells
Dorsch, L.M., Schuldt, M., Dos Remedios, C.G, Schinkel, A.F.L, de Jong, P.L, Michels, M, … Velden, J. (2019). Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy. Cells, 8(7). doi:10.3390/cells8070741