HDAC inhibitors for muscular dystrophies: progress and prospects

Sandonà, Martina; Consalvi, Silvia; Tucciarone, Luca; Puri, Pier Lorenzo; Saccone, V.

doi:10.1517/21678707.2016.1130617

Cited by 10 publications

(8 citation statements)

References 15 publications

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“…However, glucocorticoids are highly pleiotropic molecules, affecting the physiology of practically any organ 47 and long term systemic administration is often accompanied by unwanted side effects 45,[48][49][50] . The molecular and physiological mechanisms underlying their mild beneficial effects on dystrophic patients, and adverse side effects, are poorly understood 51,52 . Prompted by the results of our screening we have characterized the effects of glucocorticoid treatment on two primary muscle progenitor cell types, fibro-adipogenic progenitors and satellites cells.…”

Section: Discussionmentioning

confidence: 99%

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Perpetuini

Giuliani

Reggio

et al. 2020

Sci Rep

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Muscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy, aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screen of 1,120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). The hit list from this screen was surprisingly enriched with compounds from the glucocorticoid (GCs) chemical class, drugs that are known to promote adipogenesis in vitro and in vivo. To shed light on these data, three GCs identified in our screening efforts were characterized by different approaches. We found that like dexamethasone, budesonide inhibits adipogenesis induced by insulin in sub-confluent FAPs. However, both drugs have a pro-adipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. Gene expression analysis demonstrated that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Additionally, alongside their anti-adipogenic effect, GCs are shown to promote terminal differentiation of satellite cells. Both the anti-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor and are not observed in the presence of receptor inhibitors. Steroid administration currently represents the standard treatment for DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.In muscular dystrophies the degeneration of muscle tissue is initially compensated by efficient regeneration that neutralize muscle loss 1 . However, over time, the regenerative potential in muscles of patients affected by myopathies is impaired and myofibers repair is curbed by the formation of fibrotic scars and fat infiltrations, ultimately leading to decreased muscle function 2 . Muscle fibro-adipogenic progenitors play an important role in these processes. FAPs are muscle mesenchymal stem cells residing in the muscle fibers interstitial space. FAPs express the SCA1, CD34 and PDGFRα (CD140a) antigens while they are negative for the hematopoietic and endothelial markers, CD45 and CD31, and for the satellite marker α7 integrin (ITGA7) 2-4 . FAPs contribute to muscle regeneration by secreting IGF-1 and IL-6 3 , by facilitating the clearance of necrotic debris 5 and by promoting the formation of extra-cellular matrix 6 . In addition to this pro-regenerative roles, FAPs are responsible for the formation of ectopic tissue infiltrations ...

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Section: Discussionmentioning

confidence: 99%

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Perpetuini

Giuliani

Reggio

et al. 2020

Sci Rep

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“…The orphan drug Givinostat (S2170, formerly known as ITF2357) ( Table 7 ) is an HDAC inhibitor that increases the cross-sectional myofiber area, membrane stability, and endurance, and decreases fibrosis and inflammation in mdx muscle [ 138 , 139 , 140 ]. A Phase I/II trial (NCT01761292) in DMD patients between 8 and 10 years of age (as HDACi only has an impact early in the disease) was completed in 2017 in Italy, showing good tolerance and a decrease in necrosis, fibrosis, and fatty tissue [ 141 ]. Notably, biopsies are needed to evaluate the progression of the disease under an HDACi regimen, which involves subjecting patients to an invasive procedure [ 142 ].…”

Section: Activation Of the Cellular Pathways In Skeletal Muscle Cementioning

confidence: 99%

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

Herbelet

Rodenbach

Paepe

et al. 2020

IJMS

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In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.

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“…Previous studies identified FAPs as key cellular targets of histone deacetylase inhibitor (HDACi)-a pharmacological intervention that counters DMD progression by promoting compensatory regeneration, while inhibiting fibro-adipogenic degeneration both in preclinical studies (Minetti et al, 2006;Consalvi et al, 2011Consalvi et al, , 2013Consalvi et al, , 2016Mozzetta et al, 2013;Saccone et al, 2014;Sandoná et al, 2016) and in clinical trials (Bettica et al, 2016). While these studies indicate the pharmacological potential of HDACi to restore the regenerative environment in dystrophic muscles, by recovering physiological functional interactions between FAPs and other cellular components (Consalvi et al, 2014), the signals that mediate HDACi ability to restore physiological interactions between FAPs and other cell types in DMD muscles remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

HDAC inhibitors tune miRNAs in extracellular vesicles of dystrophic muscle‐resident mesenchymal cells

et al. 2020

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We show that extracellular vesicles (EVs) released by mesenchymal cells (i.e., fibro–adipogenic progenitors—FAPs) mediate microRNA (miR) transfer to muscle stem cells (MuSCs) and that exposure of dystrophic FAPs to HDAC inhibitors (HDACis) increases the intra‐EV levels of a subset of miRs, which cooperatively target biological processes of therapeutic interest, including regeneration, fibrosis, and inflammation. Increased levels of miR‐206 in EVs released by FAPs of muscles from Duchenne muscular dystrophy (DMD) patients or mdx mice exposed to HDACi are associated with enhanced regeneration and decreased fibrosis. Consistently, EVs from HDACi‐treated dystrophic FAPs can stimulate MuSC activation and expansion ex vivo, and promote regeneration, while inhibiting fibrosis and inflammation of dystrophic muscles, upon intramuscular transplantation in mdx mice, in vivo. AntagomiR‐mediated blockade of individual miRs reveals a specific requirement of miR‐206 for EV‐induced expansion of MuSCs and regeneration of dystrophic muscles, and indicates that cooperative activity of HDACi‐induced miRs accounts for the net biological effect of these EVs. These data point to pharmacological modulation of EV content as novel strategy for therapeutic interventions in muscular dystrophies.

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HDAC inhibitors for muscular dystrophies: progress and prospects

Cited by 10 publications

References 15 publications

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

HDAC inhibitors tune miRNAs in extracellular vesicles of dystrophic muscle‐resident mesenchymal cells

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