Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

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Mechano-signaling via Piezo1 prevents activation and p53-mediated senescence of muscle stem cells

Redox Biology, Journal Year: 2022, Volume and Issue: 52, P. 102309 - 102309

Published: April 2, 2022

Skeletal muscle stem cells (MuSCs), also called satellite cells, are instrumental for postnatal growth and skeletal regeneration. Numerous signaling cascades regulate the fate of MuSCs during regeneration but molecular mechanism by which sense mechanical stimuli remain unclear. Here, we describe that Piezo1, a mechanosensitive ion channel, keeps in quiescent state prevents senescence. Absence Piezo1 induces precocious activation MuSCs, attenuates proliferation, impairs differentiation, essentially abolishing efficient replenishment MuSC pool. Furthermore, discovered inactivation results compensatory up-regulation T-type voltage-gated Ca2+ channels, leading to increased influx, strongly NOX4 expression via cPKC. Elevated Piezo1-deficient increases ROS levels DNA damage, causing P53-dependent cellular senescence cell death. The importance P53/P21-axis mediating Piezo1-dependent defects was confirmed pharmacological inhibition P53 mice, abrogates normalizes Our findings uncover an essential role Piezo1-mediated mechano-signaling maintaining quiescence preventing Reduced due decreased physical activity aging may contribute increase senescent decline numbers geriatric mice humans.

Language: Английский

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Autophagy in muscle regeneration: potential therapies for myopathies

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2022, Volume and Issue: 13(3), P. 1673 - 1685

Published: April 17, 2022

Language: Английский

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Insights into muscle stem cell dynamics during postnatal development

FEBS Journal, Journal Year: 2021, Volume and Issue: 289(10), P. 2710 - 2722

Published: April 3, 2021

During development, resident stem cell populations contribute to the growth and maturation of tissue organs. In skeletal muscle, muscle cells, or satellite cells (SCs), are responsible for postnatal myofibers. However, role SCs play in later stages growth, thus, when they enter a mature quiescent state is controversial. Here, we discuss current literature regarding all from birth puberty onset young adulthood. We additionally highlight implications SC loss dysfunction during developmental stages, both context experimental paradigms disease settings.

Language: Английский

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Extracellular matrix: Brick and mortar in the skeletal muscle stem cell niche

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Nov. 29, 2022

The extracellular matrix (ECM) is an interconnected macromolecular scaffold occupying the space between cells. Amongst other functions, ECM provides structural support to tissues and serves as a microenvironmental niche that conveys regulatory signals Cell-matrix adhesions, which link cytoskeleton, are dynamic multi-protein complexes containing surface receptors intracellular effectors control various downstream pathways. In skeletal muscle, most abundant tissue of body, each individual muscle fiber its associated stem cells (MuSCs) surrounded by layer referred basal lamina. core lamina consists self-assembling polymeric laminins network collagens tether proteoglycans, provide lateral crosslinking, establish collateral associations with cell receptors, serve sink reservoir for growth factors. Skeletal also contains fibrillar collagenous interstitial plays important role in determining elasticity, connects laminae other, secreting mesenchymal fibroblast-like types blood vessels. During regeneration populations expand contribute transitional fibronectin-rich regenerative instructs angiogenesis MuSC function. Here, we comprehensive overview health disease outline orchestrating

Language: Английский

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RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Sept. 20, 2021

Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within somites undergo proliferation, migration differentiation to elongate fuse into multinucleated functional myofibers. Skeletal most abundant tissue body has remarkable ability self-repair by re-activating program in stem cells, known as satellite cells. Post-transcriptional regulation gene expression mediated RNA-binding proteins critically required for development during embryogenesis homeostasis adult. Differential subcellular localization activity orchestrates target at multiple levels regulate different steps myogenesis. Dysfunctions these post-transcriptional regulators impair homeostasis, but also cause defects motor neurons or neuromuscular junction, resulting degeneration disease. Many proteins, such members blind-like (MBNL) CUG-BP ETR-3-like factors (CELF) families, display both overlapping distinct targets Thus they function either cooperatively antagonistically coordinate myoblast proliferation differentiation. Evidence accumulating dynamic interplay their regulatory may control progression well cell quiescence activation. Moreover, role modification far less understood compared with transcription involved specification Here we review past achievements recent advances understanding functions development, regeneration disease, aim identify fundamental questions are still open further investigations.

Language: Английский

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CRISPR/Cas9/AAV9-mediated in vivo editing identifies MYC regulation of 3D genome in skeletal muscle stem cell

Stem Cell Reports, Journal Year: 2021, Volume and Issue: 16(10), P. 2442 - 2458

Published: Sept. 16, 2021

Skeletal muscle satellite cells (SCs) are stem responsible for development and regeneration. Although CRISPR/Cas9 has been widely used, its application in endogenous SCs remains elusive. Here, we generate mice expressing Cas9 achieve robust editing juvenile at the postnatal stage through AAV9-mediated short guide RNA (sgRNA) delivery. Additionally, reveal that quiescent resistant to CRISPR/Cas9-mediated editing. As a proof of concept, demonstrate efficient master transcription factor (TF) Myod1 locus using CRISPR/Cas9/AAV9-sgRNA system SCs. Application on two key TFs, MYC BCL6, unveils distinct functions SC activation Particularly, orchestrates regulating 3D genome architecture. Its depletion results strengthening topologically associating domain boundaries thus may affect gene expression. Altogether, our study establishes platform can be harnessed elucidate functionality regulators governing activities.

Language: Английский

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The muscle stem cell niche at a glance

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(24)

Published: Dec. 15, 2023

Skeletal muscle stem cells (MuSCs, also called satellite cells) are the source of robust regenerative capability this tissue. The hallmark property MuSCs at homeostasis is quiescence, a reversible state cell cycle arrest required for long-term preservation population. reside between an individual myofiber and enwrapping basal lamina, defining immediate MuSC niche. Additional types outside in interstitial space, contribute to niche function. Quiescence actively maintained by multiple niche-derived signals, including adhesion molecules presented from surface as well soluble signaling factors produced myofibers types. In Cell Science Glance article accompanying poster, we present most recent information on how signals promote quiescence provide perspectives further research.

Language: Английский

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Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

eLife, Journal Year: 2024, Volume and Issue: 12

Published: April 25, 2024

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation depletion Pax7 + satellite cells (SCs), we found that the pool SCs integrity junctions (NMJs) maintained in EOMs. In cell sorting profiles, derived from G93A denervation-related activation, EOMs display spontaneous (non-denervation-related) similar to wild-type mice. Specifically, cultured EOM contain more abundant transcripts axon guidance molecules, including Cxcl12 , along with sustainable renewability than counterparts under differentiation pressure. co-culture assays, AAV-delivery G93A-hindlimb SC-derived myotubes enhances motor neuron extension innervation, recapitulating innervation capacity myotubes. fed sodium butyrate (NaBu) supplementation exhibited less NMJ loss muscles. Additionally, displayed elevated expression improved following NaBu treatment vitro. Thus, NaBu-induced transcriptomic changes resembling patterns may contribute beneficial effects observed More broadly, distinct profile offer novel therapeutic targets slow functional decay provide possible ‘response biomarkers’ pre-clinical clinical studies.

Language: Английский

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The mini-IDLE 3D biomimetic culture assay enables interrogation of mechanisms governing muscle stem cell quiescence and niche repopulation

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Dec. 20, 2022

Adult skeletal muscle harbours a population of stem cells (MuSCs) that are required for repair after tissue injury. In youth, MuSCs return to reversible state cell-cycle arrest termed ‘quiescence’ injury resolution. Conversely, some in aged remain semi-activated, causing premature response injuries results incomplete and eventual cell depletion. Regulating this balance between MuSC quiescence activation may hold the key restoring homeostasis with age, but is incompletely understood. To fill gap, we developed simple tractable vitro method, rapidly inactivate freshly isolated from young murine muscle, them quiescent-like at least 1-week, which name mini-IDLE ( I nactivation D ormancy LE veraged vitro). This was achieved by introducing into 3D bioartificial niche comprised thin sheet mouse myotubes, demonstrate provides minimal cues necessary induce quiescence. With different starting numbers MuSCs, assay revealed cellular heterogeneity population-level adaptations converged on common repopulation density; behaviours previously observed only vivo. Quiescence-associated hallmarks included Pax7 + CalcR DDX6 MyoD - c-FOS signature, morphologies, polarized markers. Leveraging high-content bioimaging pipelines, relationship morphology fate signatures possible real-time morphology-based screening. When using they displayed aberrant proliferative activities delayed inactivation kinetics, among other quiescence-associated defects show partially rescued wortmannin treatment. Thus, offers an unprecedented opportunity systematically investigate long-standing queries areas such as regulation pool size functional within population, uncover regulators youth age.

Language: Английский

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