Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy

Spreafico, M.; Cafora, Marco; Bragato, Cinzia; Capitanio, Daniele; Marasca, Federica; Bodega, Beatrice; Palma, Clara De; Mora, Marina; Gelfi, Cecilia; Marozzi, Anna; Pistocchi, Anna

doi:10.1016/j.phrs.2021.105750

Cited by 20 publications

(21 citation statements)

References 56 publications

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“…Western Blot analysis was performed to evaluate the acetylation profile of a DMD zebrafish model: the results have demonstrated that the treatment with compound 1 produced an increase in α-tubulin (a marker of microtubules stability). Moreover, the assessment of cytoskeleton architecture in human DMD myoblast confirmed that HDAC8 inhibition has a crucial role in the maintenance of the skeletal muscle histomorphology [ 54 ]. Taken together, these results validated HDAC8 as a potential therapeutic target to tackle DMD.…”

Section: Involvement Of Hdac8 In Different Diseasesmentioning

confidence: 99%

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Fontana

Cursaro

Carullo

et al. 2022

IJMS

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Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators.

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Section: Involvement Of Hdac8 In Different Diseasesmentioning

confidence: 99%

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Fontana

Cursaro

Carullo

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Among the class of HDACs, HDAC8 is reported to have a unique structure as it lacks the C-terminal (aa 50–111) protein-binding domain and possesses a flexible L1 loop in the proximity of the active site, which allows it to accommodate different substrates ( Somoza et al, 2004 ). HDAC8 upregulation has been observed during the differentiation of human DMD myoblast cells ( Spreafico et al, 2021 ). The specific inhibition of HDAC8 via PCI34051 results in a significant increase of the fusion index, suggesting the role of HDAC8 in DMD pathology ( Spreafico et al, 2021 ).…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

“…HDAC8 upregulation has been observed during the differentiation of human DMD myoblast cells ( Spreafico et al, 2021 ). The specific inhibition of HDAC8 via PCI34051 results in a significant increase of the fusion index, suggesting the role of HDAC8 in DMD pathology ( Spreafico et al, 2021 ). HDAC8 expression was also observed in vivo by using zebrafish as a model organism.…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

Modeling neuromuscular diseases in zebrafish

Singh

Patten

2022

Front. Mol. Neurosci.

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Neuromuscular diseases are a diverse group of conditions that affect the motor system and present some overlapping as well as distinct clinical manifestations. Although individually rare, the combined prevalence of NMDs is similar to Parkinson’s. Over the past decade, new genetic mutations have been discovered through whole exome/genome sequencing, but the pathogenesis of most NMDs remains largely unexplored. Little information on the molecular mechanism governing the progression and development of NMDs accounts for the continual failure of therapies in clinical trials. Different aspects of the diseases are typically investigated using different models from cells to animals. Zebrafish emerges as an excellent model for studying genetics and pathogenesis and for developing therapeutic interventions for most NMDs. In this review, we describe the generation of different zebrafish genetic models mimicking NMDs and how they are used for drug discovery and therapy development.

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“…There is tentative evidence to suggest a link between cytoskeletal dynamics and nuclear mechanotransduction in DMD. Recently, a study revealed a link between gene regulation and the cytoskeleton in DMD 126 . Here, they showed the deleterious upregulation of histone deacetylase 8 (HDAC8), that they selectively inhibited, improving skeletal muscle function.…”

Section: Introductionmentioning

confidence: 99%

“…Here, they showed the deleterious upregulation of histone deacetylase 8 (HDAC8), that they selectively inhibited, improving skeletal muscle function. Interestingly, inhibition of HDAC8 led to increased acetylation of α-tubulin that restored cytoskeletal architecture in the myotubes of DMD patients 126 .…”

Section: Introductionmentioning

confidence: 99%

The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction

2022

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Dystrophin is the central protein of the dystrophin-glycoprotein complex (DGC) in skeletal and heart muscle cells. Dystrophin connects the actin cytoskeleton to the extracellular matrix (ECM). Severing the link between the ECM and the intracellular cytoskeleton has a devastating impact on the homeostasis of skeletal muscle cells, leading to a range of muscular dystrophies. In addition, the loss of a functional DGC leads to progressive dilated cardiomyopathy and premature death. Dystrophin functions as a molecular spring and the DGC plays a critical role in maintaining the integrity of the sarcolemma. Additionally, evidence is accumulating, linking the DGC to mechanosignalling, albeit this role is still less understood. This review article aims at providing an up-to-date perspective on the DGC and its role in mechanotransduction. We first discuss the intricate relationship between muscle cell mechanics and function, before examining the recent research for a role of the dystrophin glycoprotein complex in mechanotransduction and maintaining the biomechanical integrity of muscle cells. Finally, we review the current literature to map out how DGC signalling intersects with mechanical signalling pathways to highlight potential future points of intervention, especially with a focus on cardiomyopathies.

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Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy

Cited by 20 publications

References 56 publications

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Modeling neuromuscular diseases in zebrafish

The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction

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