The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy

Ralph Knöll, Masahiko Hoshijima, Hal M. Hoffman, Veronika Person, Ilka Lorenzen-Schmidt, Marie Louise Bang, Takeharu Hayashi, Nobuyuki Shiga, Hideo Yasukawa, Wolfgang Schaper, William McKenna, Mitsuhiro Yokoyama, Nicholas J. Schork, Jeffrey H. Omens, Andrew D. McCulloch, Akinori Kimura, Carol C. Gregorio, Wolfgang Poller, Jutta Schaper, Heinz P. SchultheissKenneth R. Chien

Research output: Contribution to journalArticle

579 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)943-955
Number of pages13
JournalCell
Volume111
Issue number7
DOIs
StatePublished - Dec 27 2002

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Knöll, R., Hoshijima, M., Hoffman, H. M., Person, V., Lorenzen-Schmidt, I., Bang, M. L., Hayashi, T., Shiga, N., Yasukawa, H., Schaper, W., McKenna, W., Yokoyama, M., Schork, N. J., Omens, J. H., McCulloch, A. D., Kimura, A., Gregorio, C. C., Poller, W., Schaper, J., ... Chien, K. R. (2002). The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell, 111(7), 943-955. https://doi.org/10.1016/S0092-8674(02)01226-6