Analysis of genes regulated by DUX4 via oxidative stress reveals potential therapeutic targets for treatment of facioscapulohumeral dystrophy

Karpukhina, Anna; Galkin, Ivan I.; Ma, Yinxing; Dib, Carla; Zinovkin, Roman A.; Pletjushkina, Olga Yu.; Chernyak, Boris V.; Попова, Е. Н.; Vassetzky, Yegor S.

doi:10.1016/j.redox.2021.102008

Cited by 15 publications

(14 citation statements)

References 47 publications

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“…Finally, DUX4 gene expression was found increased by oxidative stress and this phenomenon was mediated through the DNA damage response pathway highlighting a vicious circle occurring between DUX4 and oxidative stress [220]. Moreover, a recent study showed that a subset of genes was deregulated by DUX4 indirectly through oxidative stress [221]. Thus, we can hypothesize that in FSHD, oxidative stress could stabilize the HIF-1α pathway which could by itself further contribute to amplify oxidative stress.…”

Section: Oxidative Stressmentioning

confidence: 90%

“…Interestingly, Losmapimod, the first compound currently in clinical trial for FSHD is a p38MAPK inhibitor, and this kinase can regulate HIF1α signaling [236]. Moreover, oxidative stress was found to induce DUX4 expression [219] while the resulting oxidative stress induced additional toxic genes [221]. Agents that reduce oxidative stress allow survival of DUX4 expressing cells [204,237,238] and antioxidant complementation was tested in a clinical trial for FSHD [202]: these antioxidants might also affect HIF-1α which is stabilized by ROS.…”

Section: Pharmacological Hif-1α Modulators In Mdsmentioning

confidence: 99%

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Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

Nguyen

Conotte

Belayew

et al. 2021

IJMS

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Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.

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Section: Oxidative Stressmentioning

confidence: 90%

Section: Pharmacological Hif-1α Modulators In Mdsmentioning

confidence: 99%

Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

Nguyen

Conotte

Belayew

et al. 2021

IJMS

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“…In this regard, a transcriptome analysis in DUX4-express oblasts identified 200 genes relevant for the FSHD pathogenesis that are deregu DUX4 indirectly, through OS [162]. Interestingly, silencing one of such genes man restore the differentiation ability of DUX4-expressing myoblasts [162]. Mutations in proteins that critically regulate skeletal muscle integrity and homeostasis can cause myofiber damage with consecutive accumulation of inflammatory cells that produce ROS.…”

Section: Oxidative Stress In Muscular Dystrophiesmentioning

confidence: 99%

“…However, recent analyses show that the D4Z4 hypomethylation did not correlate with the disease status [ 160 , 161 ] and, instead, it seems to be due to the chromatin structure present in the contracted allele [ 161 ]. Immortalized human myoblasts expressing DUX4 exhibit high levels of ROS [ 162 ], and in turn, OS increases the DUX4 expression [ 163 ]. In this regard, a transcriptome analysis in DUX4-expressing myoblasts identified 200 genes relevant for the FSHD pathogenesis that are deregulated by DUX4 indirectly, through OS [ 162 ].…”

Section: Oxidative Stress In Muscular Dystrophiesmentioning

confidence: 99%

“…Immortalized human myoblasts expressing DUX4 exhibit high levels of ROS [ 162 ], and in turn, OS increases the DUX4 expression [ 163 ]. In this regard, a transcriptome analysis in DUX4-expressing myoblasts identified 200 genes relevant for the FSHD pathogenesis that are deregulated by DUX4 indirectly, through OS [ 162 ]. Interestingly, silencing one of such genes managed to restore the differentiation ability of DUX4-expressing myoblasts [ 162 ].…”

Section: Oxidative Stress In Muscular Dystrophiesmentioning

confidence: 99%

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Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies

et al. 2022

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Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs in clude Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy. These and other MDs are caused by mutations in genes that encode proteins responsible for the structure and function of skeletal muscles, such as components of the dystrophin-glycoprotein-complex that connect the sarcomeric-actin with the extracellular matrix, allowing contractile force transmission and providing stability during muscle contraction. Consequently, in dystrophic conditions in which such proteins are affected, muscle integrity is disrupted, leading to local inflammatory responses, oxidative stress, Ca2+-dyshomeostasis and muscle degeneration. In this scenario, dysregulation of connexin hemichannels seem to be an early disruptor of the homeostasis that further plays a relevant role in these processes. The interaction between all these elements constitutes a positive feedback loop that contributes to the worsening of the diseases. Thus, we discuss here the interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets.

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Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: Metabolic stress as potential therapeutic target

et al. 2022

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Analysis of genes regulated by DUX4 via oxidative stress reveals potential therapeutic targets for treatment of facioscapulohumeral dystrophy

Cited by 15 publications

References 47 publications

Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies

Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: Metabolic stress as potential therapeutic target

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