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Cellular microenvironments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors.

Abstract
The mechanisms underlying the cell response to mechanical forces are crucial for muscle development and functionality. We aim to determine whether mutations of the LMNA gene (which encodes lamin A/C) causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts embedded in soft matrix did not align along the gel axis, whereas control myoblasts did. LMNA-mutated myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft two-dimensional (2D) and/or static three-dimensional (3D) conditions, LMNA-mutated myoblasts showed enhanced activation of the yes-associated protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. siRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in LMNA-mutated myoblasts.
AuthorsAnne T Bertrand, Simindokht Ziaei, Camille Ehret, Hélène Duchemin, Kamel Mamchaoui, Anne Bigot, Michèle Mayer, Susana Quijano-Roy, Isabelle Desguerre, Jeanne Lainé, Rabah Ben Yaou, Gisèle Bonne, Catherine Coirault
JournalJournal of cell science (J Cell Sci) Vol. 127 Issue Pt 13 Pg. 2873-84 (Jul 01 2014) ISSN: 1477-9137 [Electronic] England
PMID24806962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014. Published by The Company of Biologists Ltd.
Chemical References
  • Adaptor Proteins, Signal Transducing
  • LMNA protein, human
  • Lamin Type A
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
Topics
  • Adaptor Proteins, Signal Transducing (genetics, metabolism)
  • Cellular Microenvironment (physiology)
  • Humans
  • Lamin Type A (genetics, metabolism)
  • Microscopy, Confocal
  • Mutation
  • Myoblasts (cytology, metabolism)
  • Phosphoproteins (genetics, metabolism)
  • Signal Transduction
  • Transcription Factors
  • YAP-Signaling Proteins

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