title: 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.
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Bertrand
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Simindokht
authors.initials: S
authors.lastname: Ziaei
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Ehret
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Duchemin
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mamchaoui
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bigot
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Centre de Référence des maladies neuromusculaire de l'Est Parisien, Service de Service de Neuropédiatrie, F-75013, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Mayer
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Paris Ile-de-France Ouest - Site Raymond Poincaré, F-92380 Garches, France.
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Centre de Référence des Maladies Neuromusculaires, Unité de Neuropédiatrie, F-75013, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Lainé
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France.
authors.forename: Rabah
authors.initials: R
authors.lastname: Ben Yaou
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris F-75013, France.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.affiliation: Institut National de la Santé et de la recherche Médicale, UMR_S 974, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France CNRS, UMR 7215, F-75013 Paris, France Institut de Myologie, Paris F-75013, France c.coirault@institut-myologie.org.
authors.forename: Catherine
authors.initials: C
authors.lastname: Coirault
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D060833:Cellular Microenvironment / Q000502:physiology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494847:LMNA protein, human; D034904:Lamin Type A; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: Cell microenvironment; LMNA; Mechanosensitivity; Muscular dystrophy; Yes-associated protein