Changes in calsequestrin, <scp>TNF</scp>‐α, <scp>TGF</scp>‐β and MyoD levels during the progression of skeletal muscle dystrophy in <i>mdx</i> mice: a comparative analysis of the quadriceps, diaphragm and intrinsic laryngeal muscles

Maranhão, Juliana Barros; Moreira, Drielen de Oliveira; Maurício, Adriana Fogagnolo; Carvalho, Samara Camaçarí de; Ferretti, Renato; Pereira, Juliana Vianna; Neto, Humberto Santo; Marques, Maria Júlia

doi:10.1111/iep.12142

Cited by 21 publications

(18 citation statements)

References 45 publications

(112 reference statements)

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“…We observed a leftward shift in the frequency distribution of dystrophic muscle fibre size and a concomitant increase in the variability of fibre size. These observations are consistent with and extend our previous findings [12,17] and those of others [49,50], revealing substantial diaphragm muscle pathology in young (8 week old) mdx mice.…”

Section: Discussionsupporting

confidence: 93%

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

et al. 2019

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Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementation on respiratory system performance in mdx mice. Eight-week-old male wild type (n = 10) and mdx (n = 20) mice were studied; a subset of mdx (n = 10) received 1% NAC in the drinking water for 14 days. We assessed breathing, diaphragm, and external intercostal electromyogram (EMG) activities and inspiratory pressure during ventilatory and non-ventilatory behaviours. Diaphragm muscle structure and function, cytokine concentrations, glutathione status, and mRNA expression were determined. Diaphragm force-generating capacity was impaired in mdx compared with wild type. Diaphragm muscle remodelling was observed in mdx, characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued mdx diaphragm function. Collagen content and immune cell infiltration were decreased in mdx + NAC compared with mdx diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in mdx plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mdx mice. We reveal that NAC treatment improved mdx diaphragm force-generating capacity associated with beneficial anti-inflammatory and anti-fibrotic effects. These data support the potential use of NAC as an adjunctive therapy in human dystrophinopathies.

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Section: Discussionsupporting

confidence: 93%

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

et al. 2019

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“…) and mdx mice (Barros Maranhão et al . ). Inflammation occurs due to muscle fibre damage as a result of dystrophin deficiency.…”

Section: Discussionmentioning

confidence: 97%

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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“…Regarding the inflammatory process, it has been reported that inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) play a major role in the DMD phenotype [ 5 ]. In mdx mice, the experimental model of DMD [ 6 ], the TNF-α content has been well characterized and shown to have increased in the diaphragm muscle where inflammation is generally greater in this model [ 7 – 9 ]. The IL-1β also contributes towards muscular dystrophy, leading to the initiation and continuation of the muscle pathology in DMD [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Dystrophic phenotype improvement in the diaphragm muscle of mdx mice by diacerhein

et al. 2017

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Chronic inflammation and oxidative stress are striking features of Duchenne muscular dystrophy disease. Diacerhein is an anthraquinone, which exhibits anti-inflammatory and antioxidant properties. Based on their actions, the present study evaluated the effects of diacerhein against myonecrosis, oxidative stress and inflammatory response in the diaphragm muscle of mdx mice and compared these results to current treatment widely used in DMD patients, with a main focus on the impact of prednisone. The results demonstrated that diacerhein treatment prevented muscle damage indicated by a decrease in the IgG uptake by muscle fibers, lower CK levels in serum, reduction of fibers with central nuclei with a concomitant increase in fibers with peripheral nuclei. It also had an effect on the inflammatory process, decreasing the inflammatory area, macrophage staining and TNF-α and IL-1β content. Regarding oxidative stress, diacerhein treatment was effective in reducing the ROS and lipid peroxidation in the diaphragm muscle from mdx mice. Compared to prednisone treatment, our findings demonstrated that diacerhein treatment improved the dystrophic phenotype in the diaphragm muscle of mdx mice similar to that of glucocorticoid therapy. In this respect, this work suggests that diacerhein has a potential use as an alternative drug in dystrophinopathy treatment and recommends that its anti-inflammatory and antioxidants properties in the dystrophic muscle should be better understood.

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Changes in calsequestrin, TNF‐α, TGF‐β and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: a comparative analysis of the quadriceps, diaphragm and intrinsic laryngeal muscles

Cited by 21 publications

References 45 publications

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

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

Dystrophic phenotype improvement in the diaphragm muscle of mdx mice by diacerhein

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