Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?

Autor:	Villarreal-Salazar M; Mitochondrial and Neuromuscular Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain., Santalla A; Universidad Pablo de Olavide, Sevilla, Spain., Real-Martínez A; Mitochondrial and Neuromuscular Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain., Nogales-Gadea G; Grup de Recerca en Malalties Neuromusculars i Neuropediàtriques, Department of Neurosciences, Institut d'Investigacio en Ciencies de la Salut Germans Trias i Pujol i Campus Can Ruti, Universitat Autònoma de Barcelona, Badalona, Spain., Valenzuela PL; Physical Activity and Health Research Group ('PaHerg'), Research Institute of the Hospital 12 de Octubre ('imas12'), Madrid, Spain., Fiuza-Luces C; Physical Activity and Health Research Group ('PaHerg'), Research Institute of the Hospital 12 de Octubre ('imas12'), Madrid, Spain., Andreu AL; EATRIS, European Infrastructure for Translational Medicine, Amsterdam, Netherlands., Rodríguez-Aguilera JC; Universidad Pablo de Olavide, Sevilla, Spain; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, Sevilla, Spain., Martín MA; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Mitochondrial and Neuromuscular Diseases Laboratory, 12 de Octubre Hospital Research Institute (i+12), Madrid, Spain., Arenas J; Mitochondrial and Neuromuscular Diseases Laboratory, 12 de Octubre Hospital Research Institute (i+12), Madrid, Spain., Vissing J; Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Lucia A; Faculty of Sport Sciences, European University, Madrid, Spain., Krag TO; Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: thomas.krag@regionh.dk., Pinós T; Mitochondrial and Neuromuscular Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. Electronic address: tomas.pinos@vhir.org.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2022 Dec; Vol. 66, pp. 101648. Date of Electronic Publication: 2022 Nov 28.
DOI:	10.1016/j.molmet.2022.101648
Abstrakt:	Background: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO 2peak )), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. Methods: We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO 2peak in patients (both sexes, N = 145) and healthy controls (N = 133). Results: Besides corroborating very poor VO 2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. Conclusions: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses. (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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