Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

• Published in: International journal of molecular sciences Vol. 22; no. 1; p. 306
• Main Authors: Owens, Daniel, Messéant, Julien, Moog, Sophie, Viggars, Mark, Ferry, Arnaud, Mamchaoui, Kamel, Lacène, Emmanuelle, Roméro, Norma, Brull, Astrid, Bonne, Gisèle, Butler-Browne, Gillian, Coirault, Catherine
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.12.2020; MDPI
• Subjects: Animals; Biopsy; Cell adhesion & migration; Cell Communication; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell division; Cytoskeleton; Disease Models, Animal; Extracellular matrix; Fluorescent Antibody Technique; Gene Expression; Genes; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Human health and pathology; Humans; Lamin Type A - genetics; Lamin Type A - metabolism; Life Sciences; Mechanical properties; Mice; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - growth & development; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophies, Limb-Girdle - etiology; Muscular Dystrophies, Limb-Girdle - metabolism; Muscular Dystrophies, Limb-Girdle - pathology; Muscular dystrophy; Musculoskeletal system; Mutation; Neuromuscular Junction - metabolism; Phenotype; Protein expression; Protein synthesis; Proteins; Signal Transduction; Stem cells; Transcription Factors - genetics; Transcription Factors - metabolism; nuclear envelope; YAP; satellite cell; mechanotransduction; muscle growth
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22010306

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.