<i>In vivo</i> neutralization of <scp>IL</scp>‐6 receptors ameliorates gastrointestinal dysfunction in dystrophin‐deficient <i>mdx</i> mice

Manning, Jennifer; Buckley, Maria M.; O’Halloran, Ken D.; O’Malley, Dervla

doi:10.1111/nmo.12803

Cited by 15 publications

(22 citation statements)

References 49 publications

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“…Urocortin, a corticoid releasing factor receptor agonist, functions similarly to β2-agonists by elevating cAMP to inhibit calapins. Urocortin 2 administered by 6 subcutaneous injections over 2 weeks rescued mdx diaphragm muscle force loss compared to saline treatment 69 , and was also found to improve mdx smooth muscle GI motility 70 . Urocortins have also shown efficacy in treating heart failure 71 , and thus may elicit both skeletal and cardiac muscle benefits in DMD.…”

Section: Promoting Muscle Massmentioning

confidence: 89%

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Spinazzola

Kunkel

2016

Expert Opinion on Orphan Drugs

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Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.

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Section: Promoting Muscle Massmentioning

confidence: 89%

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Spinazzola

Kunkel

2016

Expert Opinion on Orphan Drugs

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“…), to normalize function of gastrointestinal smooth muscle (Manning et al . ) and exert modest effects on improving diaphragm force (Manning et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…The doses and treatment protocol were chosen based on previous studies by our research group (Manning et al . , ). Drug treatment consisted of a total of six consecutive subcutaneous injections to the scruff of the neck, each on alternate days over the course of 2 weeks beginning at 6 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

Recovery of respiratory function in mdx mice co‐treated with neutralizing interleukin‐6 receptor antibodies and urocortin‐2

Burns

Canavan

Rowland

et al. 2018

The Journal of Physiology

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The mdx mouse model of Duchenne muscular dystrophy shows evidence of hypoventilation and pronounced diaphragm dysfunction. Six-week-old male mdx (n = 32) and wild-type (WT; n = 32) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (xIL-6R; 0.2 mg kg ) and corticotrophin-releasing factor receptor 2 agonist (urocortin-2; 30 μg kg ) subcutaneously over 2 weeks. Breathing and diaphragm muscle contractile function (ex vivo) were examined. Diaphragm structure was assessed using histology and immunofluorescence. Muscle cytokine concentration was determined using a multiplex assay. Minute ventilation and diaphragm muscle peak force at 100 Hz were significantly depressed in mdx compared with WT. Drug treatment completely restored ventilation in mdx mice during normoxia and significantly increased mdx diaphragm force- and power-generating capacity. The number of centrally nucleated muscle fibres and the areal density of infiltrates and collagen content were significantly increased in mdx diaphragm; all indices were unaffected by drug co-treatment. The abundance of myosin heavy chain (MyHC) type IIx fibres was significantly decreased in mdx diaphragm; drug co-treatment preserved MyHC type IIx complement in mdx muscle. Drug co-treatment increased the cross-sectional area of MyHC type I and IIx fibres in mdx diaphragm. The cytokines IL-1β, IL-6, KC/GRO and TNF-α were significantly increased in mdx diaphragm compared with WT. Drug co-treatment significantly decreased IL-1β and increased IL-10 in mdx diaphragm. Drug co-treatment had no significant effect on WT diaphragm muscle structure, cytokine concentrations or function. Recovery of breathing and diaphragm force in mdx mice was impressive in our studies, with implication for human dystrophinopathies.

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“…The doses and treatment protocol were chosen based on previous studies (Manning et al . , ). Treatment consisted of six s.c .…”

Section: Methodsmentioning

confidence: 99%

Restoration of pharyngeal dilator muscle force in dystrophin‐deficient (mdx) mice following co‐treatment with neutralizing interleukin‐6 receptor antibodies and urocortin 2

Burns

Rowland

Canavan

et al. 2017

Experimental Physiology

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What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg ) and corticotrophin-releasing factor receptor 2 agonist (urocortin 2; 30 μg kg ) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The areal density of infiltrates and collagen content were significantly increased in mdx sternohyoid; both indices were unaffected by drug treatment. The abundance of myosin heavy chain type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved myosin heavy chain type IIb complement in mdx muscle. The chemokines macrophage inflammatory protein 2, interferon-γ-induced protein 10 and macrophage inflammatory protein 3α were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT sternohyoid. Recovery of contractile function was impressive in our study, with implications for Duchenne muscular dystrophy. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remain to be elucidated.

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In vivo neutralization of IL‐6 receptors ameliorates gastrointestinal dysfunction in dystrophin‐deficient mdx mice

Abstract: These findings confirm the importance of dystrophin in normal GI function and implicate IL-6 as an important regulator of GI motility in the mdx mouse. Inhibition of IL-6 signaling may offer a potential new therapeutic strategy for treating DMD-associated GI symptoms.

Cited by 15 publications

References 49 publications

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Recovery of respiratory function in mdx mice co‐treated with neutralizing interleukin‐6 receptor antibodies and urocortin‐2

Restoration of pharyngeal dilator muscle force in dystrophin‐deficient (mdx) mice following co‐treatment with neutralizing interleukin‐6 receptor antibodies and urocortin 2

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