Laminopathies constitute a clinically heterogeneous group of diseases caused by mutations in the LMNA gene, which encodes lamins A and C, two proteins of the nuclear envelope. Together with the nuclear lamina, these A-type lamins form a fibrous network that largely determines the mechanical properties of the nucleus. Among the pathologies associated with LMNA mutations, characterized by skeletal and cardiac muscle involvement, are autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). The latter is distinguished by a particularly severe muscle phenotype, with atrophy beginning very early and marked contractures. These features suggest that the mutations may compromise skeletal muscle growth, but the underlying pathophysiological mechanisms have remained poorly understood.
To investigate this hypothesis, the authors combined three levels of analysis: human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, a mouse model, and patient biopsies. The animal model relied on heterozygous Lmna+/ΔK32 mice, carrying the same mutation as that observed in patients, which strengthens the translational relevance of the data. Hypertrophy was induced by functional overload of the plantaris muscle, achieved after tenotomy of the soleus and gastrocnemius, while protein synthesis was measured using the SUnSET method and the neuromuscular junction was analyzed on isolated fibers.
In vitro, mutated human muscle stem cells displayed impaired myogenic fusion, associated with disorganization of cadherin/β-catenin adhesion complexes, whose role is essential for sensing and transmitting forces between cells. In LMNA-CMD mice, skeletal muscle proved unable to hypertrophy in response to functional overload, owing to a defect in the fusion of activated MuSCs, deficient protein synthesis, and abnormal remodeling of the neuromuscular junction. Furthermore, myotubes subjected to stretch and overloaded muscle fibers carrying LMNA-CMD mutations exhibited aberrant mechanical regulation of the YAP (yes-associated protein) protein. These abnormalities in muscle stem cell activation and YAP signaling were also found in patient biopsies. Notably, such phenotypes were not reproduced in EDMD models, which are nonetheless related but less severe.
By cross-referencing in vitro, in vivo, and human-sample approaches, this work establishes that LMNA-CMD mutations disrupt skeletal muscle mechanotransduction pathways, thereby implicating A-type lamins in the regulation of muscle growth.