Tranilast administration reduces fibrosis and improves fatigue resistance in muscles of mdx dystrophic mice

Swiderski, Kristy; Todorov, Michelle; Gehrig, Stefan M.; Naim, Timur; Chee, Annabel; Stapleton, David; Koopman, René; Lynch, Gordon S.

doi:10.1186/1755-1536-7-1

Cited by 30 publications

(34 citation statements)

References 32 publications

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“…The concentration and quality of RNA samples were determined using Nanodrop 2000 spectrophotometer (Thermo Scientific, Waltham, MA, USA). Real-time RT-PCR was performed as described previously [30] using the following forward and reverse primer sequences: SOCS3, 5′-GCTGGCCAAAGAAATAACCA-3′ and 5′- AGCTCACCAGCCTCATCTGT-3′. Relative gene expression was calculated using the expression 2 −ΔCT , normalized to total complementary DNA (cDNA) content as determined using Qubit 2.0 Fluorometer (Life Technologies, Carlsbad, CA, USA), as described previously [12].…”

Section: Methodsmentioning

confidence: 99%

“…The concentration and quality of RNA samples was determined using Nanodrop 2000 spectrophotometer (Thermo Scientific, Waltham, MA, USA). Real-time RT-PCR was performed as described previously [30] using the following forward and reverse primer sequences: MCK, 5′-CACCATGCCGTTCGGCAACA-3′ and 5′-GGTTGTCCACCCCAGTCT-3′; SOCS3, 5′-GCTGGCCAAAGAAATAACCA-3′ and 5′-AGCTCACCAGCCTCATCTGT-3′; Pax7, 5′-GGAAAACCAGTGTGCCATCT-3′ and 5′-CCTTGTCTTTGGCACCATTT-3′; MyoD, 5′-AGTGAATGAGGCCTTCGAGA-3′ and 5′-GCATCTGAGTCGCCACTGTA-3′; Myogenin, 5′-CACTCCCTTACGTCCATCGT-3′ and 5′-CAGGACAGCCCCACTTAAAA-3′; IL-6, 5′-CCGGAGAGGAGACTTCACAG-3′ and 5′-TCCACGATTTCCCAGAGAAC-3′; TNF-α, 5′-GGCCTTCCTACCTTCAGACC-3′ and 5′-AGCAAAAGAGGAGGCAACAA-3′; IFN-γ, 5′-ACTGGCAAAAGGATGGTGAC-3′ and 5′-TGAGCTCATTGAATGCTTGG-3′; F4/80, 5′-CATCAGCCATGTGGGTACAG-3′ and 5′-CATCACTGCCTCCACTAGCA-3′; CD68, 5′-TCCAAGCCCAAATTCAAATC-3′ and 5′-ATTGTATTCCACCGCCATGT-3′. Gene expression was quantified using a cycle threshold (C T ) method.…”

Section: Methodsmentioning

confidence: 99%

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Muscle-specific deletion of SOCS3 increases the early inflammatory response but does not affect regeneration after myotoxic injury

et al. 2016

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BackgroundMuscles of old animals are injured more easily and regenerate poorly, attributed in part to increased levels of circulating pro-inflammatory cytokines. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade is a key mediator of inflammatory cytokine action, and signaling via this pathway is increased in muscles with aging. As a negative regulator of JAK/STAT signaling, a key mediator of myogenic proliferation and differentiation, altered expression of suppressor of cytokine signaling (SOCS3) is likely to have important consequences for muscle regeneration. To model this scenario, we investigated the effect of SOCS3 deletion within mature muscle fibers on injury and repair. We tested the hypothesis that reduced SOCS3 function would alter the inflammatory response and impair muscle regeneration after myotoxic injury.MethodsMice with a specific deletion of SOCS3 within mature skeletal muscle fibers were used to assess the effect of SOCS3 deletion on muscle injury and repair. Twelve-week-old or 24-month-old SOCS3 muscle-specific knockout (SOCS3 MKO) mice and littermate controls were either left uninjured or injured with a single injection of notexin (10 μg/ml) into the right tibialis anterior (TA) muscle. At 1, 2, 3, 5, 7, or 14 days post-injury, the right TA muscle was excised and subjected to histological, western immunoblotting, and gene expression analyses. Force production and fatigue were assessed in uninjured muscles and at 7 days post-notexin injury.ResultsIn uninjured muscles, SOCS3 deletion decreased force production during fatigue but had no effect on the gross or histological appearance of the TA muscles. After notexin injury, deletion of SOCS3 increased STAT3 phosphorylation at day 1 and increased the mRNA expression of the inflammatory cytokine TNF-α, and the inflammatory cell markers F4/80 and CD68 at day 2. Gene expression analysis of the regeneration markers Pax7, MyoD, and Myogenin indicated SOCS3 deletion had no effect on the progression of muscle repair after notexin injury. Inflammation and regeneration were also unchanged in the muscles of 24-month-old SOCS3 MKO mice compared with control.ConclusionsLoss of SOCS3 expression in mature muscle fibers increased the inflammatory response to myotoxic injury but did not impair muscle regeneration in either adult or old mice. Therefore, reduced SOCS3 expression in muscle fibers is unlikely to underlie impaired muscle regeneration. Further investigation into the role of SOCS3 in other cell types involved in muscle repair is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0108-4) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Muscle-specific deletion of SOCS3 increases the early inflammatory response but does not affect regeneration after myotoxic injury

et al. 2016

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“…The mdx mouse is a very useful model but fails to reproduce key symptoms of DMD patients such as muscular weakness 2 . Thus, although several immunotherapies were successful in mdx mice, such as intravenous immunoglobulin 18 , anti-TNFα antibodies 19 , IL-6 blocking 20 , tranilast 21 , heme oxygenase-1 (HO-1) inducers 22 , IL-1 receptor antagonist 23 and IL-2 complexes to amplify CD4 + Tregs 12 , their potential effect in DMD patients is uncertain. Dmd mdx rats reproduce skeletal and cardiac muscular weakness at early time points and develop skeletal and cardiac muscle tissue lesions that resemble those observed in DMD patients 3, 4 .…”

Section: Discussionmentioning

confidence: 99%

Immunological characterization of a rat model of Duchenne’s disease and demonstration of improved muscle strength after anti-CD45RC antibody treatment

Ouisse¹,

Remy²,

Lafoux³

et al. 2018

Preprint

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Duchenne muscular dystrophy (DMD) has as standard pharmacological therapy with corticoisteroids (CS) that decrease inflammation and immune responses present in patients and animal models. CS have however limited efficacy and important and numerous side effects. Therefore, there is a need for new anti-inflammatory and pro-tolerogenic treatments that could replace or decrease doses of CS. We first assessed the status of immune system of dystrophin-deficient rats (Dmdmdx) that closely reproduce the phenotype of DMD patients. Dmdmdx rats showed increased leukocyte infiltration in skeletal and cardiac muscles, containing mostly macrophages but also T cells, and increased expression of several cytokines. Anti-CD45RC Monoclonal antibody (Mab) treatment induced immune tolerance in models of organ transplantation and GVHD (Graft Versus Host Disease). We observed that muscles and blood of DMD patients contained T CD4+ and CD8+ expressing high levels of CD45RChigh cells. Treatment of young Dmdmdx rats with anti-CD45RC MAb corrected skeletal muscle strength associated to a depletion of effectors CD45RChigh T cells with no obvious side-effects. Prednisolone treatment of Dmdmdx rats similarly increased skeletal muscle strength and was also associated to a depletion of effectors CD45RChigh cells but resulted in severe weight loss.Overall, Dmdmdx rats display important immune inflammatory response and thus represent a useful model to analyze new anti-inflammatory and tolerogenic treatments for DMD. As an example, a new treatment with anti-CD45RC antibodies improved muscle strength in Dmdmdx rats as prednisolone did but without side effects. Anti-CD45RC therapy could complement other therapies in DMD patients.

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“…It was found that dominant-negative inhibition of endogenous TRPV2 in mdx mice suppressed the calcium increase in muscle fibers and eased dystrophic pathology, that is, the increased number of central nucleus and fiber size variability/fibrosis/apoptosis, elevated serum creatine kinase levels, and reduced muscle performance 33. Tranilast, a clinically used antiallergic drug, is also known to be a TRPV2 blocker experimentally,34 and its administration was found to be efficacious in reducing serum creatine kinase levels in mdx mice35 and fibrosis in mdx skeletal muscles, leading to improved resistance to muscle fatigue 36…”

Section: Potential Drugs Targeting Inflammatory Mechanisms In Dmdmentioning

confidence: 99%

Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

Miyatake

Shimizu‐Motohashi

Takeda

et al. 2016

DDDT

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Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

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Tranilast administration reduces fibrosis and improves fatigue resistance in muscles of mdx dystrophic mice

Cited by 30 publications

References 32 publications

Muscle-specific deletion of SOCS3 increases the early inflammatory response but does not affect regeneration after myotoxic injury

Muscle-specific deletion of SOCS3 increases the early inflammatory response but does not affect regeneration after myotoxic injury

Immunological characterization of a rat model of Duchenne’s disease and demonstration of improved muscle strength after anti-CD45RC antibody treatment

Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

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