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

M Villarreal-Salazar, Santalla A, A Real-Martínez, G Nogales-Gadea, Valenzuela Pl, C Fiuza-Luces, Andreu Al, J C Rodríguez-Aguilera, M A Martín, Arenas J, Vissing J, Lucia A, Krag To*, Pinós T*

*Corresponding author af dette arbejde


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 (VO2peak)), 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 characteristicscontent, biogenesis, ultrastructureand network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N = 145) and healthy controls (N = 133).

RESULTS: Besides corroborating very poor VO2peak 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 componentsactin microfilaments, microtubules and intermediate filamentsthereby 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 calsequestrinwith 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.

TidsskriftMolecular Metabolism
Sider (fra-til)1-15
Antal sider15
StatusUdgivet - dec. 2022


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