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BNIP3 Is Involved in Muscle Fiber Atrophy in Late-Onset Pompe Disease Patients

  • Ana Carrasco-Rozas
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain
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  • Esther Fernández-Simón
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    John Walton Muscular Dystrophy Research Center, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, United Kingdom
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  • Xavier Suárez-Calvet
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
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  • Patricia Piñol-Jurado
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    John Walton Muscular Dystrophy Research Center, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, United Kingdom
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  • Jorge Alonso-Pérez
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain
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  • Noemí de Luna
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
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  • Benedikt Schoser
    Affiliations
    Friedrich-Baur-Institute, Department of Neurology, LMU Klinikum, Munich, Germany
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  • Peter Meinke
    Affiliations
    Friedrich-Baur-Institute, Department of Neurology, LMU Klinikum, Munich, Germany
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  • Cristina Domínguez-González
    Affiliations
    Department of Neurology, Neuromuscular Unit, 12 de Octubre University Hospital, Madrid, Spain; Research Institute of Hospital 12 de Octubre (i+12), Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Spain
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  • Aurelio Hernández-Laín
    Affiliations
    Department of Pathology (Neuropathology), 12 de Octubre University Hospital, Madrid, Spain; Research Institute of Hospital 12 de Octubre (i+12), Madrid, Spain
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  • Carmen Paradas
    Affiliations
    Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

    Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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  • Eloy Rivas
    Affiliations
    Department of Pathology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
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  • Isabel Illa
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
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  • Montse Olivé
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
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  • Eduard Gallardo
    Correspondence
    Address correspondence to Jordi Díaz-Manera, John Walton Muscular Dystrophy Research Center, Newcastle University, Center for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom; or Eduard Gallardo, Neuromuscular Disorders Unit, Research Institute of the Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 77, 08041 Barcelona, Spain.
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
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  • Jordi Díaz-Manera
    Correspondence
    Address correspondence to Jordi Díaz-Manera, John Walton Muscular Dystrophy Research Center, Newcastle University, Center for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom; or Eduard Gallardo, Neuromuscular Disorders Unit, Research Institute of the Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 77, 08041 Barcelona, Spain.
    Affiliations
    Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Spain

    John Walton Muscular Dystrophy Research Center, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, United Kingdom

    Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
    Search for articles by this author
      Late-onset Pompe disease (LOPD) is a rare genetic disorder produced by mutations in the GAA gene and is characterized by progressive muscle weakness. LOPD muscle biopsies show accumulation of glycogen along with the autophagic vacuoles associated with atrophic muscle fibers. The expression of molecules related to muscle fiber atrophy in muscle biopsies of LOPD patients was studied using immunofluorescence and real-time PCR. BNIP3, a well-known atrogene, was identified as a potential mediator of muscle fiber atrophy in LOPD muscle biopsies. We observed that vacuolated fibers in LOPD patient muscle biopsies were smaller than nonvacuolated fibers and expressed BNIP3. Our data suggested that BNIP3 expression is regulated by inhibition of the AKT–mammalian target of rapamycin pathway, leading to phosphorylation of ULK1 at Ser317 by AMP-activated protein kinase. We studied myoblasts and myotubes obtained from LOPD patients and age-matched controls to confirm these results using different molecular techniques. Myotubes derived from LOPD patients were likewise smaller and expressed BNIP3. Conclusively, transfection of BNIP3 into control myotubes leads to myotube atrophy. These findings suggest a cascade that starts with the inhibition of the AKT–mammalian target of rapamycin pathway and activation of BNIP3 expression, leading to progressive muscle fiber atrophy. Our results open the door to potential new treatments targeting BNIP3 to reduce its deleterious effects on muscle fiber atrophy in Pompe disease.
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