Myopalladin is upregulated in dilated cardiomyopathies patients and myopalladin knockout mice develop cardiac dilation and dysfunction following pressure overload

Background: Myopalladin (MYPN) is a 145 kDa striated musclespecific sarcomeric protein belonging to the palladin (PALLD)/MYPN/ myotilin family of actin-associated immunoglobulin-containing proteins in the Z-line. MYPN gene mutations are causative for dilated (DCM), hypertrophic and restrictive cardiomyopathy. Methods and results: To determine whether MYPN expression is altered during disease, we performed qRT-PCR on cardiac biopsies from DCM (n=8) and ischemic cardiomyopathy (ICM) (n=8) patients vs. healthy subjects (n=5). This revealed a 2.7 fold upregulation of MYPN mRNA in DCM patients as well as a similar 2.5 fold upregulation of PALLD mRNA, encoding the 200 kDa striated muscle-specific PALLD isoform, structurally homologous to MYPN. In contrast, levels of transcripts encoding the ubiquitously expressed smaller isoforms of PALLD were unaltered. As previously reported also MYPN’s interaction partner ANKRD1/CARP was 4.5 fold upregulated in DCM patients. To determine the functional role of MYPN, we generated MYPN knockout (MKO) mice, which had a normal life span but were significantly smaller compared to wildtype (WT) controls. Cardiac analyses of MKO mice showed the development of progressive cardiac dilation and decreased fractional shortening starting from 4 months of age, which was associated decreased tension generation and increased resting tension in ventricular myofibrils. Following transaortic constriction, MKO mice exhibited a normal hypertrophic response, but developed severe cardiac dilation and systolic dysfunction, associated with upregulation of CARP protein and reduced CSQ2 protein and Akt473 phosphorylation levels. Conclusion: Furthermore, analyses on isolated adult cardiomyocytes showed reduced sarcomere contractility, and calcium spark frequency and amplitude in MKO mice compared to WT, consistent with altered calcium signaling