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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Article Info
Publication History
Published online: May 20, 2022
Accepted:
May 4,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Supported by Fundación Isabel Gemio funding (J.D.M. and E.G.), the Spanish Ministry of Health , Fondo Europeo de Desarrollo Regional -FEDER, Instituto de Salud Carlos III (Spain) FIS ( PI18/1525 ) (J.D.M. and X.S.C.), Instituto de Salud Carlos III (Sara Borrell fellowship, CD18/00195; X.S.C.), and cofunded by European Regional Development Fund / European Social Fund , “investing in your future” (X.S.C.).
E.G. and J.D.-M. contributed equally to this work.
Disclosures: A.C.-R., X.S.-C., J.A.-P., N.d.L., I.I., M.O., E.G., and J.D.-M. are members of the European Reference Network for Neuromuscular Disease and members of XUECs (Xarxes d'Unitats d'Expertesa Clínica en Malalties Minoritàries).
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© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
