<scp>AdipoRon</scp>, a new therapeutic prospect for Duchenne muscular dystrophy

Abou‐Samra, Michel; Selvais, Charlotte; Boursereau, R.; Lecompte, Sophie; Noël, Laurence; Brichard, Sonia

doi:10.1002/jcsm.12531

Cited by 34 publications

(58 citation statements)

References 63 publications

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“…Some of these beneficial effects of ApN/AdipoRon have been translated to humans. We found that ApN/AdipoRon supplementation retained its anti-inflammatory properties in DMD human myotubes [56,57,103] and induced a shift in the secretion of downstream myokines toward a less inflammatory profile. Indeed, secretome analysis from myotubes revealed that ApN down-regulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) [57].…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 75%

“…dye solution into muscles mirrored the strengthening of sarcolemmal integrity [56]. All these beneficial effects of ApN have recently been reproduced by AdipoRon, an agonist of ApN receptor given orally for 2 months to young mdx mice [103] (see Section 6.3).…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 96%

“…As in healthy muscle, the mechanisms leading to the protective effects of ApN/AdipoRon in DMD involved the activation of the AdipoR1-AMPK-SIRT1-PGC-1α axis both in vivo (mdx mice) or in vitro (human dystrophic myotubes) [56,57,103] (Figure 4). Silencing each component of this cascade abrogated the effects of ApN/AdipoRon.…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

“…PPARα could also contribute to repress NF-κB [61]. Moreover, restoration of the myogenic program could result from attenuation of inflammation [56,103] as well as from insulin-sensitizing properties or p38 MAPK activation [68,69]. Eventually, enhanced activity of PGC-1α will lead to up-regulation of several target genes contributing to the protection afforded by ApN/AdipoRon in DMD.…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

“…Our latest study has brought to light the beneficial and protective effects of AdipoRon on the dystrophic skeletal muscle in mdx mice and in human DMD myotubes. Indeed, AdipoRon, mainly though AdipoR1-AMPK signaling, significantly mitigated skeletal muscle inflammation, oxidative stress, and damage, while markedly improving its regeneration and function [103].…”

Section: Adiporonmentioning

confidence: 99%

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Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

Abou‐Samra

Selvais

Dubuisson

et al. 2020

IJMS

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Adiponectin (ApN) is a hormone abundantly secreted by adipocytes and it is known to be tightly linked to the metabolic syndrome. It promotes insulin-sensitizing, fat-burning, and anti-atherosclerotic actions, thereby effectively counteracting several metabolic disorders, including type 2 diabetes, obesity, and cardiovascular diseases. ApN is also known today to possess powerful anti-inflammatory/oxidative and pro-myogenic effects on skeletal muscles exposed to acute or chronic inflammation and injury, mainly through AdipoR1 (ApN specific muscle receptor) and AMP-activated protein kinase (AMPK) pathway, but also via T-cadherin. In this review, we will report all the beneficial and protective properties that ApN can exert, specifically on the skeletal muscle as a target tissue. We will highlight its effects and mechanisms of action, first in healthy skeletal muscle including exercised muscle, and second in diseased muscle from a variety of pathological conditions. In the end, we will go over some of AdipoRs agonists that can be easily produced and administered, and which can greatly mimic ApN. These interesting and newly identified molecules could pave the way towards future therapeutic approaches to potentially prevent or combat not only skeletal muscle disorders but also a plethora of other diseases with sterile inflammation or metabolic dysfunction.

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Section: Duchenne Muscular Dystrophymentioning

confidence: 75%

Section: Duchenne Muscular Dystrophymentioning

confidence: 96%

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

Section: Adiporonmentioning

confidence: 99%

See 3 more Smart Citations

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

Abou‐Samra

Selvais

Dubuisson

et al. 2020

IJMS

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AdipoRon enhances healthspan in middle‐aged obese mice: striking alleviation of myosteatosis and muscle degenerative markers

Selvais¹,

Carrizosa

Nachit³

et al. 2022

J cachexia sarcopenia muscle

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Background Obesity among older adults has increased tremendously. Obesity accelerates ageing and predisposes to age‐related conditions and diseases, such as loss of endurance capacity, insulin resistance and features of the metabolic syndrome. Namely, ectopic lipids play a key role in the development of nonalcoholic fatty liver disease (NAFLD) and myosteatosis, two severe burdens of ageing and metabolic diseases. Adiponectin (ApN) is a hormone, mainly secreted by adipocytes, which exerts insulin‐sensitizing and fat‐burning properties in several tissues including the liver and the muscle. Its overexpression also increases lifespan in mice. In this study, we investigated whether an ApN receptor agonist, AdipoRon (AR), could slow muscle dysfunction, myosteatosis and degenerative muscle markers in middle‐aged obese mice. The effects on myosteatosis were compared with those on NAFLD. Methods Three groups of mice were studied up to 62 weeks of age: One group received normal diet (ND), another, high‐fat diet (HFD); and the last, HFD combined with AR given orally for almost 1 year. An additional group of young mice under an ND was used. Treadmill tests and micro‐computed tomography (CT) were carried out in vivo. Histological, biochemical and molecular analyses were performed on tissues ex vivo. Bodipy staining was used to assess intramyocellular lipid (IMCL) and lipid droplet morphology. Results AR did not markedly alter diet‐induced obesity. Yet, this treatment rescued exercise endurance in obese mice (up to 2.4‐fold, P < 0.05), an event that preceded the improvement of insulin sensitivity. Dorsal muscles and liver densities, measured by CT, were reduced in obese mice (−42% and −109%, respectively, P < 0.0001), suggesting fatty infiltration. This reduction tended to be attenuated by AR. Accordingly, AR significantly mitigated steatosis and cellular ballooning at liver histology, thereby decreasing the NALFD activity score (−30%, P < 0.05). AR also strikingly reversed IMCL accumulation either due to ageing in oxidative fibres (types 1/2a, soleus) or to HFD in glycolytic ones (types 2x/2b, extensor digitorum longus) (−50% to −85%, P < 0.05 or less). Size of subsarcolemmal lipid droplets, known to be associated with adverse metabolic outcomes, was reduced as well. Alleviation of myosteatosis resulted from improved mitochondrial function and lipid oxidation. Meanwhile, AR halved aged‐related accumulation of dysfunctional proteins identified as tubular aggregates and cylindrical spirals by electron microscopy (P < 0.05). Conclusions Long‐term AdipoRon treatment promotes ‘healthy ageing’ in obese middle‐aged mice by enhancing endurance and protecting skeletal muscle and liver against the adverse metabolic and degenerative effects of ageing and caloric excess.

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Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo

et al. 2021

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Aims/hypothesis Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. Methods Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. Results In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1β (51%, p < 0.001) and TGFβ (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-κB-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNFα (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1β, IL-18, IL-6 and IL-10. Conclusions/interpretation AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation. Graphical abstract

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AdipoRon, a new therapeutic prospect for Duchenne muscular dystrophy

Cited by 34 publications

References 63 publications

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

AdipoRon enhances healthspan in middle‐aged obese mice: striking alleviation of myosteatosis and muscle degenerative markers

Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo

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