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Article

Muscle Proteomic Profile before and after Enzyme Replacement Therapy in Late-Onset Pompe Disease

1
Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, 20097 Milano, Italy
2
Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milano, Italy
3
Department of Biomedical Sciences for Health, University of Milan, 20090 Milano, Italy
4
IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy
5
Department of Medicine and Surgery, PhD Program in Neuroscience, University of Milano-Bicocca, 20126 Milano, Italy
6
Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: María Luz Couce
Int. J. Mol. Sci. 2021, 22(6), 2850; https://doi.org/10.3390/ijms22062850
Received: 10 February 2021 / Revised: 7 March 2021 / Accepted: 8 March 2021 / Published: 11 March 2021
(This article belongs to the Special Issue Omics Technologies in Rare Diseases)
Mutations in the acidic alpha-glucosidase (GAA) coding gene cause Pompe disease. Late-onset Pompe disease (LOPD) is characterized by progressive proximal and axial muscle weakness and atrophy, causing respiratory failure. Enzyme replacement therapy (ERT), based on recombinant human GAA infusions, is the only available treatment; however, the efficacy of ERT is variable. Here we address the question whether proteins at variance in LOPD muscle of patients before and after 1 year of ERT, compared withhealthy age-matched subjects (CTR), reveal a specific signature. Proteins extracted from skeletal muscle of LOPD patients and CTR were analyzed by combining gel based (two-dimensional difference gel electrophoresis) and label-free (liquid chromatography-mass spectrometry) proteomic approaches, and ingenuity pathway analysis. Upstream regulators targeting autophagy and lysosomal tethering were assessed by immunoblotting. 178 proteins were changed in abundance in LOPD patients, 47 of them recovered normal level after ERT. Defects in oxidative metabolism, muscle contractile protein regulation, cytoskeletal rearrangement, and membrane reorganization persisted. Metabolic changes, ER stress and UPR (unfolded protein response) contribute to muscle proteostasis dysregulation with active membrane remodeling (high levels of LC3BII/LC3BI) and accumulation of p62, suggesting imbalance in the autophagic process. Active lysosome biogenesis characterizes both LOPD PRE and POST, unparalleled by molecules involved in lysosome tethering (VAMP8, SNAP29, STX17, and GORASP2) and BNIP3. In conclusion this study reveals a specific signature that suggests ERT prolongation and molecular targets to ameliorate patient’s outcome. View Full-Text
Keywords: pompe disease; sarcopenia; autophagy; rare disease; proteomics; mass spectrometry pompe disease; sarcopenia; autophagy; rare disease; proteomics; mass spectrometry
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MDPI and ACS Style

Moriggi, M.; Capitanio, D.; Torretta, E.; Barbacini, P.; Bragato, C.; Sartori, P.; Moggio, M.; Maggi, L.; Mora, M.; Gelfi, C. Muscle Proteomic Profile before and after Enzyme Replacement Therapy in Late-Onset Pompe Disease. Int. J. Mol. Sci. 2021, 22, 2850. https://doi.org/10.3390/ijms22062850

AMA Style

Moriggi M, Capitanio D, Torretta E, Barbacini P, Bragato C, Sartori P, Moggio M, Maggi L, Mora M, Gelfi C. Muscle Proteomic Profile before and after Enzyme Replacement Therapy in Late-Onset Pompe Disease. International Journal of Molecular Sciences. 2021; 22(6):2850. https://doi.org/10.3390/ijms22062850

Chicago/Turabian Style

Moriggi, Manuela, Daniele Capitanio, Enrica Torretta, Pietro Barbacini, Cinzia Bragato, Patrizia Sartori, Maurizio Moggio, Lorenzo Maggi, Marina Mora, and Cecilia Gelfi. 2021. "Muscle Proteomic Profile before and after Enzyme Replacement Therapy in Late-Onset Pompe Disease" International Journal of Molecular Sciences 22, no. 6: 2850. https://doi.org/10.3390/ijms22062850

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