The Role of Integrin β1D Mislocalization in the Pathophysiology of Calpain 3-Related Limb–Girdle Muscular Dystrophy

• Published in: Cells (Basel, Switzerland) Vol. 14; no. 6; p. 446
• Main Authors: Valls, Andrea, Ruiz-Roldán, Cristina, Immanuel, Jenita, Alonso-Martín, Sonia, Gallardo, Eduard, Fernández-Torrón, Roberto, Bonilla, Mario, Lersundi, Ana, Hernández-Laín, Aurelio, Domínguez-González, Cristina, Vílchez, Juan Jesús, Iruzubieta, Pablo, López de Munain, Adolfo, Sáenz, Amets
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.03.2025; MDPI
• Subjects: Analysis; Antibodies; Blood vessels; Calpain; Calpain - genetics; Calpain - metabolism; calpain 3; costamere; Extracellular matrix; Extracellular Matrix - metabolism; Female; Focal adhesion kinase; Genetic aspects; Growth factors; Homeostasis; Humans; Integrin beta1 - metabolism; integrin β1; Integrins; Invoices; Kinases; LGMDR1; limb-girdle muscular dystrophy; Male; Microscopy; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophies, Limb-Girdle - genetics; Muscular Dystrophies, Limb-Girdle - metabolism; Muscular Dystrophies, Limb-Girdle - pathology; Muscular Dystrophies, Limb-Girdle - physiopathology; Muscular dystrophy; Musculoskeletal system; Patients; Protein Isoforms - metabolism; Proteins; Sarcolemma; Sarcolemma - metabolism; Signal Transduction; Talin; Talin - metabolism; United States; Massachusetts; Germany; Spain; United States > US; integrin β1; LGMDR1; costamere; calpain 3; limb-girdle muscular dystrophy
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells14060446

Limb–girdle muscular dystrophy R1 (LGMDR1) is characterized by progressive proximal muscle weakness due to mutations in the CAPN3 gene. Little is known about CAPN3’s function in muscle, but its loss results in aberrant sarcomere formation. Human muscle structure was analyzed in this study, with observations including integrin β1D isoform (ITGβ1D) mislocalization, a lack of Talin-1 (TLN1) in the sarcolemma and the irregular expression of focal adhesion kinase (FAK) in LGMDR1 muscles, suggesting a lack of integrin activation with an altered sarcolemma, extracellular matrix (ECM) assembly and signaling pathway deregulation, which may cause frailty in LGMDR1 muscle fibers. Additionally, altered nuclear morphology, centrosome distribution and microtubule organization have been found in muscle cells derived from LGMDR1 patients.