Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities

Elife. 2023 Mar 16:12:e78629. doi: 10.7554/eLife.78629.

Abstract

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 (MKO) mice exhibited a similar phenotype as MKO mice, suggesting that MYPN does not compensate for the loss of PALLD in cPKO mice. Altered transcript levels of MYPN and PALLD isoforms were found in myocardial tissue from human dilated and ischemic cardiomyopathy patients, whereas their protein expression levels were unaltered.

Keywords: biochemistry; cardiomyopathy; chemical biology; heart; intercalated disc; molecular biophysics; mouse; myopalladin; palladin; sarcomere; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies* / genetics
  • Cardiomyopathy, Dilated*
  • Cytoskeletal Proteins* / genetics
  • Cytoskeletal Proteins* / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Proteins / metabolism
  • Myocardium / metabolism
  • Protein Isoforms / genetics

Substances

  • Cytoskeletal Proteins
  • Muscle Proteins
  • palladin protein, mouse
  • Protein Isoforms

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.