Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality

Christopher T. Pappas, Rachel M. Mayfield, Christine Henderson, Nima Jamilpour, Cathleen Cover, Zachary Hernandez, Kirk R. Hutchinson, Miensheng Chu, Ki Hwan Nam, Jose M. Valdez, Pak Kin Wong, Henk L. Granzier, Carol C. Gregorio

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Leiomodin 2 (Lmod2) is an actin-binding protein that has been implicated in the regulation of striated muscle thin filament assembly; its physiological function has yet to be studied. We found that knockout of Lmod2 in mice results in abnormally short thin filaments in the heart. We also discovered that Lmod2 functions to elongate thin filaments by promoting actin assembly and dynamics at thin filament pointed ends. Lmod2-KO mice die as juveniles with hearts displaying contractile dysfunction and ventricular chamber enlargement consistent with dilated cardiomyopathy. Lmod2- null cardiomyocytes produce less contractile force than wild type when plated on micropillar arrays. Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood. Thus, to our knowledge, Lmod2 is the first identified mammalian protein that functions to elongate actin filaments in the heart; it is essential for cardiac thin filaments to reach a mature length and is required for efficient contractile force and proper heart function during development.

Original languageEnglish (US)
Pages (from-to)13573-13578
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number44
DOIs
StatePublished - Nov 3 2015

Keywords

  • Actin-thin filaments
  • Cardiomyopathy
  • Cytoskeletal dynamics

ASJC Scopus subject areas

  • General

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