f82ef52fc508fac17b2dc0ea4edf3332 321771.pdf 6d541385d3fea265db1fc29f9d17dbe1855dc77d 321771.pdf 593c02761042094485b9174230f7b6d70fffb795d94a0974d706e5235ea2da39 321771.pdf Title: The Role of Integrin 1D Mislocalization in the Pathophysiology of Calpain 3-Related Limb–Girdle Muscular Dystrophy Subject: 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 1D isoform (ITG1D) 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. Keywords: limb-girdle muscular dystrophy; LGMDR1; calpain 3; integrin 1; costamere Author: Andrea Valls, Cristina Ruiz-Roldán, Jenita Immanuel, Sonia Alonso-Martín, Eduard Gallardo, Roberto Fernández-Torrón, Mario Bonilla, Ana Lersundi, Aurelio Hernández-Laín, Cristina Domínguez-González, Juan Jesús Vílchez, Pablo Iruzubieta, Adolfo López de Munain and Amets Sáenz Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Mon Mar 17 10:02:35 2025 CET ModDate: Mon Mar 17 10:33:02 2025 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 35 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 32164538 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JPUAMM+EURM10 Type 1 Builtin yes yes yes 10 0 ZYYJXI+EURB10 Type 1 Builtin yes yes yes 15 0 XDUKBX+VnURWPalladioL Type 1 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Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 1263 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Primary Human Skeletal Muscle Culture Destination: subsection.2.1 Item: Title: Immunofluorescence of Muscle Sections Destination: subsection.2.2 Item: Title: Immunofluorescence of Cell Cultures Destination: subsection.2.3 Item: Title: Wound-Healing (WH) Assay in CD56- Cells Destination: subsection.2.4 Item: Title: Confocal Microscopy Analysis and Statistics Destination: subsection.2.5 Item: Title: Results Destination: section.3 Children: Item: Title: Costamere Proteins Are Fiber-Type-Dependent and Also Present in the Endothelial Tissue Destination: subsection.3.1 Item: Title: Abnormal Distribution of ITG1D and TLN1 in LGMDR1 Patients’ Muscle Destination: subsection.3.2 Item: Title: Abnormal Blood Vessel Morphology in LGMDR1 Patients’ Muscles Destination: subsection.3.3 Item: Title: TLN1 Localizes in the Nucleolus in CD56- Cells, Myoblasts, Myotubes and Muscle Destination: subsection.3.4 Item: Title: Abnormal Nuclear Morphology in LGMDR1 Patient Samples Destination: subsection.3.5 Item: Title: Centrosome Organization Is Impaired in LGMDR1 Cells Destination: subsection.3.6 Item: Title: Aberrant Mitosis in LGMDR1 CD56- Cells Destination: subsection.3.7 Item: Title: Discussion Destination: section.4 Children: Item: Title: Fiber-Type Distribution in Healthy Muscle Destination: subsection.4.1 Item: Title: Vascular Endothelium Alteration in LGMDR1 Destination: subsection.4.2 Item: Title: Implications of Altered ITG1D Distribution in LGMDR1 Destination: subsection.4.3 Item: Title: References Destination: appendix.A. Info: Title: The Role of Integrin 1D Mislocalization in the Pathophysiology of Calpain 3-Related Limb Girdle Muscular Dystrophy Author: Andrea Valls, Cristina Ruiz-Roldán, Jenita Immanuel, Sonia Alonso-Martín, Eduard Gallardo, Roberto Fernández-Torrón, Mario Bonilla, Ana Lersundi, Aurelio Hernández-Laín, Cristina Domínguez-González, Juan Jesús Vílchez, Pablo Iruzubieta, Adolfo López de Munain and Amets Sáenz Subject: 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 1D isoform (ITG1D) 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. 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