Ablation of palladin in adult cardiac muscle causes cardiac dilation and systolic dysfunction

Introduction: Palladin (PALLD) belongs to the PALLD/myopalladin (MYPN)/myotilin (MYOT) family of immunoglobulin-containing proteins in the sarcomeric Z-line associated with the actin cytoskeleton. While MYPN and MYOT are expressed in striated and skeletal muscle, respectively, PALLD is ubiquitously expressed in several isoforms. The longest PALLD isoform is expressed predominantly in striated muscle and shows high structural homology to MYPN. However, while MYPN gene mutations have been associated with human cardiomyopathies, the role of PALLD in the heart has remained unknown, partly due to embryonic lethality of PALLD knockout (KO) mice. To study the role of PALLD in the heart, we generated constitutive (cPKOc) and inducible (cPKOi) cardiac specific PALLD KO mice as well as constitutive double KO mice for PALLD and MYPN (cPKOc/MKO). Methods and Results: While echocardiographic analyses revealed development of dilated cardiomyopathy (DCM) of MYPN KO (MKO) mice starting from 4 months of age, cPKOc mice exhibited no cardiac phenotype either at basal conditions or following transaortic constriction. MKO/cPKOc mice exhibited a similar phenotype as MKO mice, suggesting that MYPN and PALLD do not have overlapping functions. In contrast, induction of PALLD KO in adult cPKOi mice resulted in progressive cardiac dilation and systolic dysfunction, associated with reduced cardiomyocyte contractility (Ionoptix analysis), increased resting tension (mechanics on isolated single myofibrils), abnormal intercalated disc ultrastructure, upregulation of markers of cardiac pathological remodeling, ERK activation, and fibrosis. Conclusions: The development of a DCM phenotype in cPKOi mice induced at adult stage demonstrates that PALLD is essential for normal cardiac function and propose PALLD as a candidate gene for cardiomyopathy. In contrast, cPKOc mice exhibited no cardiac J Muscle Res Cell Motil 123 phenotype, likely due to compensatory mechanisms, which do not appear to involve its closest homologue MYPN.