Combined XIL‐6R and urocortin‐2 treatment restores <i>MDX</i> diaphragm muscle force

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

doi:10.1002/mus.25644

Cited by 8 publications

(29 citation statements)

References 65 publications

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“…) and exert modest effects on improving diaphragm force (Manning et al . ). Conversely, overexpression of IL‐6 in mdx mice promotes muscle necrosis and satellite cell exhaustion (Pelosi et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Manning et al . ), increase muscle mass (Hall et al . ) and decrease muscle damage (Reutenauer‐Patte 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%

“…; Manning et al . ). Moreover, Ucn2 has been shown to exert beneficial effects on cardiac function in healthy subjects and heart failure patients (Stirrat et al .…”

Section: Introductionmentioning

confidence: 97%

“…Combined treatment with xIL‐6R and Ucn2 restored diaphragm muscle functional deficits in mdx mice, evidenced by improved force, work and muscle shortening capacity (Manning et al . ). Similarly, a co‐treatment of xIL‐6R and Ucn2 completely recovered pharyngeal dilator (sternohyoid) muscle force and power loss in mdx mice (Burns et al .…”

Section: Introductionmentioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 97%

“…; Manning et al . ), increase muscle mass (Hall et al . ) and decrease muscle damage (Reutenauer‐Patte et al .…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…; Manning et al . ). Moreover, Ucn2 has been shown to exert beneficial effects on cardiac function in healthy subjects and heart failure patients (Stirrat et al .…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

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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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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The conventional isoproterenol-induced heart failure model does not consistently mimic the diaphragmatic dysfunction observed in patients

et al. 2020

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Heart failure (HF) impairs diaphragm function. Animal models realistically mimicking HF should feature both the cardiac alterations and the diaphragmatic dysfunction characterizing this disease. The isoproterenol-induced HF model is widely used, but whether it presents diaphragmatic dysfunction is unknown. However, indirect data from research in other fields suggest that isoproterenol could increase diaphragm function. The aim of this study was to test the hypothesis that the widespread rodent model of isoproterenol-induced HF results in increased diaphragmatic contractility. Forty C57BL/6J male mice were randomized into 2 groups: HF and healthy controls. After 30 days of isoproterenol infusion to establish HF, in vivo diaphragmatic excursion and ex vivo isolated diaphragm contractibility were measured. As compared with healthy controls, mice with isoproterenol-induced HF showed the expected changes in structural and functional echocardiographic parameters and lung edema. isoproterenol-induced HF increased in vivo diaphragm excursion (by ≈30%, p<0.01) and increased by ≈50% both ex vivo peak specific force (p<0.05) and tetanic force (p<0.05) at almost all 10–100 Hz frequencies (p<0.05), with reduced fatigue resistance (p<0.01) when compared with healthy controls. Expression of myosin genes encoding the main muscle fiber types revealed that Myh4 was higher in isoproterenol-induced HF than in healthy controls (p<0.05), suggesting greater distribution of type IIb fibers. These results show that the conventional isoproterenol-induced HF model increases diaphragm contraction, a finding contrary to what is observed in patients with HF. Therefore, this specific model seems limited for translational an integrative HF research, especially when cardio-respiratory interactions are investigated.

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Combined XIL‐6R and urocortin‐2 treatment restores MDX diaphragm muscle force

Abstract: Treatment which neutralizes peripheral IL-6 signaling and stimulates CRFR2 recovers force-generating capacity and the ability to perform mechanical work in mdx diaphragm muscle. These findings may be important in the search for therapeutic targets in DMD. Muscle Nerve 56: E134-E140, 2017.

Cited by 8 publications

References 65 publications

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

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

The conventional isoproterenol-induced heart failure model does not consistently mimic the diaphragmatic dysfunction observed in patients

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