title: The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy.
abstract: Muscle cells respond to mechanical stretch stimuli by triggering downstream signals for myocyte growth and survival. The molecular components of the muscle stretch sensor are unknown, and their role in muscle disease is unclear. Here, we present biophysical/biochemical studies in muscle LIM protein (MLP) deficient cardiac muscle that support a selective role for this Z disc protein in mechanical stretch sensing. MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein. Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization. We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure.
authors.affiliation: Institute of Molecular Medicine, Department of Medicine, University of California at San Diego, La Jolla 92093, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: Veronika
authors.initials: V
authors.lastname: Person
authors.forename: Ilka
authors.initials: I
authors.lastname: Lorenzen-Schmidt
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bang
authors.forename: Takeharu
authors.initials: T
authors.lastname: Hayashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shiga
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schaper
authors.forename: William
authors.initials: W
authors.lastname: McKenna
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Omens
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.forename: Jutta
authors.initials: J
authors.lastname: Schaper
authors.forename: Heinz P
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D064211:Connectin; D005260:Female; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008875:Middle Aged; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D009470:Muscle Spindles / Q000378:metabolism / Q000648:ultrastructure; D020125:Mutation, Missense / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D017434:Protein Structure, Tertiary / Q000235:genetics; D013314:Stress, Mechanical
chemical_list: D064211:Connectin; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C577292:TCAP protein, human; C577294:Tcap protein, mouse; C090114:cysteine and glycine-rich protein 3