Cardiac-specific knockout of Lmod2 results in a severe reduction in myofilament force production and rapid cardiac failure

Christopher T. Pappas, Gerrie P. Farman, Rachel M. Mayfield, John P. Konhilas, Carol C. Gregorio

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Leiomodin-2 (Lmod2) is a striated muscle-specific actin binding protein that is implicated in assembly of thin filaments. The necessity of Lmod2 in the adult mouse and role it plays in the mechanics of contraction are unknown. To answer these questions, we generated cardiac-specific conditional Lmod2 knockout mice (cKO). These mice die within a week of induction of the knockout with severe left ventricular systolic dysfunction and little change in cardiac morphology. Cardiac trabeculae isolated from cKO mice have a significant decrease in maximum force production and a blunting of myofilament length-dependent activation. Thin filaments are non-uniform and substantially reduced in length in cKO hearts, affecting the functional overlap of the thick and thin filaments. Remarkably, we also found that Lmod2 levels are directly linked to thin filament length and cardiac function in vivo, with a low amount (<20%) of Lmod2 necessary to maintain cardiac function. Thus, Lmod2 plays an essential role in maintaining proper cardiac thin filament length in adult mice, which in turn is necessary for proper generation of contractile force. Dysregulation of thin filament length in the absence of Lmod2 contributes to heart failure.

Original languageEnglish (US)
Pages (from-to)88-97
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume122
DOIs
StatePublished - Sep 2018

Keywords

  • Actin-thin filaments
  • Cardiomyopathy
  • Sarcomere

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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