title: Liver Kinase B1 complex acts as a novel modifier of myofilament function and localizes to the Z-disk in cardiac myocytes.
abstract: Contractile perturbations downstream of Ca(2+) binding to troponin C, the so-called sarcomere-controlled mechanisms, represent the earliest indicators of energy remodeling in the diseased heart [1]. Central to cellular energy "sensing" is the adenosine monophosphate-activated kinase (AMPK) pathway, which is known to directly target myofilament proteins and alter contractility [2-6]. We previously showed that the upstream AMPK kinase, LKB1/MO25/STRAD, impacts myofilament function independently of AMPK [5]. Therefore, we hypothesized that the LKB1 complex associated with myofilament proteins and that alterations in energy signaling modulated targeting or localization of the LKB1 complex to the myofilament. Using an integrated strategy of myofilament mechanics, immunoblot analysis, co-immunoprecipitation, mass spectroscopy, and immunofluorescence, we showed that 1) LKB1 and MO25 associated with myofibrillar proteins, 2) cellular energy stress re-distributed AMPK/LKB1 complex proteins within the sarcomere, and 3) the LKB1 complex localized to the Z-Disk and interacted with cytoskeletal and energy-regulating proteins, including vinculin and ATP Synthase (Complex V). These data represent a novel role for LKB1 complex proteins in myofilament function and myocellular "energy" sensing in the heart.
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ, USA; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Behunin
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA; Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Lopez-Pier
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Mayfield
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ, USA; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA.
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Danilo
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Lipovka
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA; Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Birch
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ, USA; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lehman
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Jil C
authors.initials: JC
authors.lastname: Tardiff
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ, USA; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, USA. Electronic address: konhilas@arizona.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Konhilas
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009119:Muscle Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000378:metabolism; D019209:Troponin C / Q000378:metabolism*
chemical_list: D019209:Troponin C; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium
keywords: Contractility; Liver Kinase B1 (LKB1); Myofibril; Myofilament; Vinculin; Z-disk