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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-11, Vol.112 (44), p.13573-13578
• Main Authors: Pappas, Christopher T., Mayfield, Rachel M., Henderson, Christine, Jamilpour, Nima, Cover, Cathleen, Hernandez, Zachary, Hutchinson, Kirk R., Chu, Miensheng, Nam, Ki-Hwan, Valdez, Jose M., Wong, Pak Kin, Granzier, Henk L., Gregorio, Carol C.
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - genetics; Actin Cytoskeleton - metabolism; Animals; Animals, Newborn; Binding sites; Biological Sciences; Cardiomyopathy; Cardiomyopathy, Dilated - embryology; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Cells, Cultured; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Fluorescence Recovery After Photobleaching; Genes, Lethal - genetics; Heart; Heart - embryology; Heart - physiopathology; Immunoblotting; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mice, Knockout; Mice, Transgenic; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Muscle Contraction - genetics; Muscle Contraction - physiology; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Myocardium - metabolism; Myocardium - pathology; Myocardium - ultrastructure; Proteins; Rodents; Sarcomeres - genetics; Sarcomeres - metabolism; Survival Analysis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1508273112

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 ofLmod2in 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 inLmod2-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.