Low aerobic capacity in McArdle disease : A role for mitochondrial network impairment?
Villarreal-Salazar, M. (Hospital Universitari Vall d'Hebron)
Santalla, A. (Universidad Pablo de Olavide)
Real-Martinez, Alberto (Hospital Universitari Vall d'Hebron)
Nogales, Gisela (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Valenzuela, P.L. (Hospital Universitario 12 de Octubre (Madrid))
Fiuza-Luces, C. (Hospital Universitario 12 de Octubre (Madrid))
Andreu, A. L. (European Infrastructure for Translational Medicine)
Rodríguez-Aguilera, J.C. (Universidad Pablo de Olavide)
Martín, M.A. (Hospital Universitario 12 de Octubre (Madrid))
Arenas, Joaquín (Hospital Universitario 12 de Octubre (Madrid))
Vissing, J. (University of Copenhagen)
Lucia, A. (European University)
Krag, T.O. (University of Copenhagen)
Pinós Figueras, Tomàs (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Fecha:	2022
Resumen:	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)), 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. 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 in patients (both sexes, N = 145) and healthy controls (N = 133). Besides corroborating very poor VO 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. 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.
Ayudas:	Instituto de Salud Carlos III PI17/02052 Instituto de Salud Carlos III PI18/00139 Instituto de Salud Carlos III PI19/01313 Instituto de Salud Carlos III PI20/00645 Ministerio de Economía y Competitividad CD14/00032
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Aerobic capacity ; Cytoskeleton and mitochondrial network ; Glycogen ; McArdle disease ; Skeletal muscle
Publicado en:	Molecular metabolism, Vol. 66 (november 2022) , ISSN 2212-8778

DOI: 10.1016/j.molmet.2022.101648
PMID: 36455789

15 p, 9.5 MB

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