期刊
JOURNAL OF CELL SCIENCE
卷 127, 期 13, 页码 2873-2884出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.144907
关键词
LMNA; Cell microenvironment; Mechanosensitivity; Muscular dystrophy; Yes-associated protein
类别
资金
- Institut National de la Sante et de la Recherche Medicale
- Sorbonne Universites-Universite Pierre et Marie Curie Paris
- Centre National de la Recherche Scientifique
- COST action (Nanonet) [BM1002]
- Association Francaise contre les Myopathies
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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