Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
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.
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Christopher T
CT
Pappas
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Rachel M
RM
Mayfield
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Christine
C
Henderson
Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721.
Nima
N
Jamilpour
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Cathleen
C
Cover
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Zachary
Z
Hernandez
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Kirk R
KR
Hutchinson
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Miensheng
M
Chu
Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721.
Ki-Hwan
KH
Nam
Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721.
Jose M
JM
Valdez
Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721.
Pak Kin
PK
Wong
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721;
Henk L
HL
Granzier
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721; gregorio@email.arizona.edu.
Carol C
CC
Gregorio
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002311:Cardiomyopathy, Dilated / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D005804:Genes, Lethal / Q000235:genetics; D006321:Heart / Q000196:embryology / Q000503:physiopathology; D015151:Immunoblotting; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
D003598:Cytoskeletal Proteins; D008164:Luminescent Proteins; D009124:Muscle Proteins; C523689:leiomodin protein, mouse
actin-thin filaments; cardiomyopathy; cytoskeletal dynamics