Key result
Palladin ablation causes progressive cardiac dilation and systolic dysfunction in adult mice.
Why the study?
MYPN mutations cause cardiomyopathies, but the cardiac role of homologous PALLD remained unknown due to embryonic lethality in knockout mice.
Does ablation of palladin cause cardiomyopathy and cardiac dysfunction in adult mice?
Does ablation of palladin cause cardiomyopathy and cardiac dysfunction in adult mice?
Palladin is essential for normal cardiac function, and its ablation in adult mice leads to progressive dilated cardiomyopathy and systolic dysfunction.
Palladin ablation induces cardiomyopathy in adult mice; hypothesis-generating for its role in human disease, requiring clinical correlation before any relevance.
Palladin (PALLD) belongs to the PALLD/myopalladin (MYPN)/myotilin family of actin-associated immunoglobulin-containing proteins in the sarcomeric Z-line. PALLD is ubiquitously expressed in several isoforms and its longest 200 kDa isoform, predominantly expressed in striated muscle, shows high structural homology to MYPN. MYPN gene mutations are associated with human cardiomyopathies, whereas the role of PALLD in the heart has remained unknown, partly due to embryonic lethality of PALLD knockout mice. In a yeast two-hybrid screening, CARP/Ankrd1 and FHOD1 were identified as novel interaction partners of PALLD’s N-terminal region. To study the role of PALLD in the heart, we generated conditional (cPKO) and inducible (cPKOi) cardiomyocyte-specific PALLD knockout mice. While cPKO mice exhibited no pathological phenotype, ablation of PALLD in adult cPKOi mice caused progressive cardiac dilation and systolic dysfunction, associated with reduced cardiomyocyte contractility, intercalated disc abnormalities, and fibrosis, demonstrating that PALLD is essential for normal cardiac function. Double cPKO and MYPN knockout mice exhibited a similar phenotype as MKO mice, suggesting that MYPN does not compensate for the loss of PALLD in cPKO mice. Transcript levels of MYPN and the PALLD long isoform were significantly increased in myocardial tissue from human dilated cardiomyopathy patients, suggesting a role of PALLD in cardiac disease.
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Mastrototaro et al. (2022) studied Dilated cardiomyopathy. Palladin (PALLD) ablation vs. Control mice was evaluated on Cardiac morphology and systolic function. Ablation of palladin in adult mice caused progressive cardiac dilation, systolic dysfunction, and intercalated disc abnormalities, demonstrating its essential role in normal cardiac function.
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