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.
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Authors | Anne 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 |
Journal | Journal of cell science
(J Cell Sci)
Vol. 127
Issue Pt 13
Pg. 2873-84
(Jul 01 2014)
ISSN: 1477-9137 [Electronic] England |
PMID | 24806962
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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