Antioxidant SkQ1 delays sarcopenia-associated damage of mitochondrial ultrastructure

Vays, V. B.; Eldarov, Chupalav; Vangely, Irina M.; Kolosova, N. G.; Bakeeva, L. E.; Vp, Skulachev

doi:10.18632/aging.100636

Cited by 41 publications

(36 citation statements)

References 21 publications

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“…Since neurodegenerative conditions and aging have been associated with chronically elevated levels of ROS, antioxidant treatments have been proposed or are currently in clinical trial [70][71][72]. In our work, we observed that HDAC4mKO mice neither increased the levels of ROS and RNS in skeletal muscle nor induced the expression and activation of the enzymes involved in the antioxidant response, 1 week following denervation.…”

Section: Discussionmentioning

confidence: 53%

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

et al. 2018

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Background: Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. Methods: To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. Results: After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitinproteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. Conclusions: These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.

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Section: Discussionmentioning

confidence: 53%

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

et al. 2018

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“…The regional differences in mitochondrial function, either as a result of damage to the mitochondria by external mechanisms or regional impairment in function, may be attenuated by the presence of connections between mitochondria in subsarcolemmal and interfibrillar regions. 42, 43 …”

Section: Metabolism and Metabolic Flexibility In The Aging Heartmentioning

confidence: 99%

Mitochondrial Metabolism in Aging Heart

Lesnefsky

Chen

Hoppel

2016

Circulation Research

263

207

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Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area there is an approximate 50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.

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“…In the current study, we used SkQ1 antioxidant, based on the plastoquinone moiety linked to dodecyltriphenylphosphonium cation that targets SkQ1 to mitochondria [26]. SkQ1 and its analogs are efficient in the prevention of some age-associated pathologies, and they have therapeutic effects in animal models of diseases associated with inflammatory response (heart, brain, and kidney ischemic injury [27, 28], pyelonephritis [29], eye diseases [30, 31], sarcopenia [32], and dermal wound healing [33]). SkQ1 delays the development of various markers of aging and prolongs the lifespan of various animals [20, 22, 34, 35].…”

Section: Introductionmentioning

confidence: 99%

Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

Zinovkin

Romaschenko

Galkin

et al. 2014

Aging

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Vascular aging is accompanied by increases in circulatory proinflammatory cytokines leading to inflammatory endothelial response implicated in early atherogenesis. To study the possible role of mitochondria-derived reactive oxygen species (ROS) in this phenomenon, we applied the effective mitochondria-targeted antioxidant SkQ1, the conjugate of plastoquinone with dodecyltriphenylphosphonium. Eight months treatment of (CBAxC57BL/6) F1 mice with SkQ1 did not prevent age-related elevation of the major proinflammatory cytokines TNF and IL-6 in serum, but completely abrogated the increase in adhesion molecule ICAM1 expression in aortas of 24-month-old animals. In endothelial cell culture, SkQ1 also attenuated TNF-induced increase in ICAM1, VCAM, and E-selectin expression and secretion of IL-6 and IL-8, and prevented neutrophil adhesion to the endothelial monolayer. Using specific inhibitors to transcription factor NF-κB and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-κB activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-κB activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit IκBα. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-κB pathway and corresponding age-related inflammatory activation of endothelium.

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Antioxidant SkQ1 delays sarcopenia-associated damage of mitochondrial ultrastructure

Cited by 41 publications

References 21 publications

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

Mitochondrial Metabolism in Aging Heart

Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

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