The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy.
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.
Knöll
Ralph
R
Institute of Molecular Medicine, Department of Medicine, University of California at San Diego, La Jolla 92093, USA.
Hoshijima
Masahiko
M
Hoffman
Hal M
HM
Person
Veronika
V
Lorenzen-Schmidt
Ilka
I
Bang
Marie-Louise
ML
Hayashi
Takeharu
T
Shiga
Nobuyuki
N
Yasukawa
Hideo
H
Schaper
Wolfgang
W
McKenna
William
W
Yokoyama
Mitsuhiro
M
Schork
Nicholas J
NJ
Omens
Jeffrey H
JH
McCulloch
Andrew D
AD
Kimura
Akinori
A
Gregorio
Carol C
CC
Poller
Wolfgang
W
Schaper
Jutta
J
Schultheiss
Heinz P
HP
Chien
Kenneth R
KR
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
D064211:Connectin; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C577292:TCAP protein, human; C577294:Tcap protein, mouse; C090114:cysteine and glycine-rich protein 3