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Owens, DJ, Messeant, J, Moog, S, Viggars, M, Ferry, A, Mamchaoui, K, Lacene, E, Romero, N, Brull, A, Bonne, G, Butler-Browne, G and Coirault, C (2020) Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth. International Journal of Molecular Sciences, 22 (1). ISSN 1661-6596
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Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth.pdf - Published Version Available under License Creative Commons Attribution. Download (7MB) | Preview |
Abstract
Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/β catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely related but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth.
| Item Type: | Article |
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| Uncontrolled Keywords: | 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences |
| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics Q Science > QP Physiology R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine R Medicine > RC Internal medicine > RC1200 Sports Medicine |
| Divisions: | Sport & Exercise Sciences |
| Publisher: | MDPI |
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| Date Deposited: | 12 Feb 2021 09:59 |
| Last Modified: | 04 Sep 2021 05:57 |
| DOI or ID number: | 10.3390/ijms22010306 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/14443 |
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