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Lookup NU author(s): Professor Jordi Diaz ManeraORCiD
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© 2022 American Society for Investigative PathologyLate-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. BCL2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a well-known atrogene, was identified as a potential mediator of muscle fiber atrophy in LOPD muscle biopsies. Vacuolated fibers in LOPD patient muscle biopsies were smaller than nonvacuolated fibers and expressed BNIP3. The current data suggested that BNIP3 expression is regulated by inhibition of the AKT–mammalian target of rapamycin pathway, leading to phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1) at Ser317 by AMP-activated protein kinase. Myoblasts and myotubes obtained from LOPD patients and age-matched controls were studied 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 led 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. These results open the door to potential new treatments targeting BNIP3 to reduce its deleterious effects on muscle fiber atrophy in Pompe disease.
Author(s): Carrasco-Rozas A, Fernandez-Simon E, Suarez-Calvet X, Pinol-Jurado P, Alonso-Perez J, de Luna N, Schoser B, Meinke P, Dominguez-Gonzalez C, Hernandez-Lain A, Paradas C, Rivas E, Illa I, Olive M, Gallardo E, Diaz-Manera J
Publication type: Article
Publication status: Published
Journal: American Journal of Pathology
Year: 2022
Volume: 192
Issue: 8
Pages: 1151-1166
Print publication date: 01/08/2022
Online publication date: 21/05/2022
Acceptance date: 04/05/2022
ISSN (print): 0002-9440
ISSN (electronic): 1525-2191
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.ajpath.2022.05.003
DOI: 10.1016/j.ajpath.2022.05.003
PubMed id: 35605642
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