Long‐term administration of the mitochondria‐targeted antioxidant mitoquinone mesylate fails to attenuate age‐related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle

Abstract

Age-related skeletal muscle dysfunction is the underlying cause of morbidity that affects up to half the population aged 80 and over. Considerable evidence indicates that oxidative damage and mitochondrial dysfunction contribute to the sarcopenic phenotype that occurs with aging. To examine this, we administered the mitochondria-targeted antioxidant mitoquinone mesylate {[10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenylphosphonium; 100 μM} to wild-type C57BL/6 mice for 15 wk (from 24 to 28 mo of age) and investigated the effects on age-related loss of muscle mass and function, changes in redox homeostasis, and mitochondrial organelle integrity and function. We found that mitoquinone mesylate treatment failed to prevent age-dependent loss of skeletal muscle mass associated with myofiber atrophy or alter a variety of in situ and ex vivo muscle function analyses, including maximum isometric tetanic force, decline in force after a tetanic fatiguing protocol, and single-fiber-specific force. We also found evidence that long-term mitoquinone mesylate administration did not reduce mitochondrial reactive oxygen species or induce significant changes in muscle redox homeostasis, as assessed by changes in 4-hydroxynonenal protein adducts, protein carbonyl content, protein nitration, and DNA damage determined by the content of 8-hydroxydeoxyguanosine. Mitochondrial membrane potential, abundance, and respiration assessed in permeabilized myofibers were not significantly altered in response to mitoquinone mesylate treatment. Collectively, these findings demonstrate that long-term mitochondria-targeted mitoquinone mesylate administration failed to attenuate age-related oxidative damage in skeletal muscle of old mice or provide any protective effect in the context of muscle aging.—Sakellariou, G. K., Pearson, T., Lightfoot, A. P., Nye, G. A., Wells, N., Giakoumaki, I. I., Griffiths, R. D., McArdle, A., Jackson, M. J. Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle.

Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice

“…Here we administered mitoQ as the mesylate salt complexed to cyclodextrin added to the drinking water, whereas in the prior study we added mitoQ bromide. However, it is doubtful that the decrease in tolerability in our current is due to this, since the mesylate salt with cyclodextrin has emerged as the apparent preferred method (Rodriguez-Cuenca et al 2010;McManus et al 2011;Mercer et al 2012;Feillet-Coudray et al 2014;Sakellariou et al 2016) and cyclodextrin is widely used in pharmacologic studies and considered to be well tolerated (McManus et al 2011).…”

“…; Sakellariou et al. ) and cyclodextrin is widely used in pharmacologic studies and considered to be well tolerated (McManus et al. ).…”

“…However, mitoQ mesylate in cyclodextrin added to drinking water at the same dose, 100 μ mol/L, for 15 weeks did not attenuate age‐related oxidative damage in muscle of C57BL/6 mice or alter mitochondrial function in permeabilized myofibers (Sakellariou et al. ). Rodriguez‐Cuenca et al.…”

Dysfonctions mitochondriales et vieillissement musculaire

“…En effet, un nombre non-négligeable d'études n'a trouvé aucune augmentation de la production mitochondriale d'EAO au cours du vieillissement musculaire, que ce soit chez l'homme [22,23] ou chez le rat [24]. Deux études récentes, qui se sont intéres-sées aux effets de la supplémentation en anti-oxydants ciblant spécifiquement les mitochondries (le MitoQ -un mimétique du coenzyme Q10 -et le SS-31 1 ), mettent également à mal l'implication d'une surproduction d'EAO dans le développement de la sarcopénie [25,26]. Dans ces 2 études, dans lesquelles les supplémentations en anti-oxydants ont été initiées avant l'apparition de la sarcopénie et maintenues pendant 15 semaines, aucun 1 De formule : D-Arg-2', 6'-diméthyltyrosine-Lys-Phe-NH 2 .…”

“…Cette technique permet donc d'étudier les mitochondries dans leur environnement naturel. effet protecteur contre la sacropénie n'a été observé, ce qui remet en cause l'importance des EAO produits par les mitochondries dans le déve-loppement de la sarcopénie [25,26]. Ainsi, bien que la plupart des études s'accordent sur le fait que le vieillissement musculaire est associé à l'apparition d'un stress oxydant, l'implication des mitochondries dans ce processus reste incertaine [56] (➜).…”