Treatment with human immunoglobulin G improves the early disease course in a mouse model of Duchenne muscular dystrophy

Zschüntzsch, Jana; Zhang, Yaxin; Klinker, Florian; G, Makosch; Klinge, Lars; Malzahn, Dörthe; Brinkmeier, Heinrich; Liebetanz, David; Schmidt, Jens

doi:10.1111/jnc.13269

Cited by 17 publications

(14 citation statements)

References 54 publications

(64 reference statements)

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“…However, with regard to muscle function, only the time to fatigue by forced treadmill running was tested; no experiments testing muscle contractile function were performed ( 40 ). Since considerable basic research and some clinical trials currently focus on improving secondary defects associated with muscular dystrophy development, such as reduction of inflammation ( 41 ) or oxidative stress ( 42 ) and modulation of the TGF-β pathway, which plays an important role in the degeneration/regeneration response ( 43 ), it will be important to study both muscle pathology and function to determine whether a therapeutic agent ameliorates disease. Ultimately, combination treatments that target both simultaneously may offer the best therapeutic approach for many types of muscular dystrophy.…”

Section: Discussionmentioning

confidence: 99%

Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

et al. 2016

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Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed γ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting γ-sarcoglycan-null/Col6a2Δex5 mice indeed exhibit reduced muscle pathology compared with γ-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in γ-sarcoglycan-null/Col6a2Δex5 mice than in γ-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in γ-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies.

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Section: Discussionmentioning

confidence: 99%

Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

et al. 2016

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“…For the comparative proteomic profiling of the membraneenriched fraction from dystrophic mice, quadriceps femoris muscle specimens from the 100-day-old mdx mouse model of Duchenne muscular dystrophy (C57BL/10 ScSn-Dmdmdx/J) and age-matched wild type C57BL/10 ScSnJ controls were obtained from the Animal Facility of the University of Greifswald, Germany (Holland et al 2015). The histological assessment of mdx quadriceps femoris muscle morphology was carried out with standardized haematoxylin/eosin staining of transverse cryosections, as previously described in detail (Carberry et al 2013;Zschüntzsch et al 2016). The entire mouse population used for experimental optimisation, comparative proteomics and verification analysis consisted of 24 animals (12 wild type versus 12 mdx mice).…”

Section: Skeletal Muscle Preparationsmentioning

confidence: 99%

“…4, demonstrating a high fraction of central nucleation and a greater variability of fibre diameters in the mdx quadriceps femoris muscle. Detailed overviews of haematoxylin and eosin stained skeletal muscles from the dystrophic mdx mouse model of Duchenne muscular dystrophy have previously been published (Carberry et al 2013), including quadriceps femoris muscle (Zschüntzsch et al 2016). Tables 3 and 4 list major muscle proteins with a significantly reduced versus increased density in dystrophic muscle, respectively.…”

Section: Comparative Proteomic Profiling Of the Membrane-enriched Framentioning

confidence: 99%

Proteomic profiling of the dystrophin complex and membrane fraction from dystrophic mdx muscle reveals decreases in the cytolinker desmoglein and increases in the extracellular matrix stabilizers biglycan and fibronectin

Murphy

Brinkmeier

Krautwald

et al. 2017

J Muscle Res Cell Motil

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The almost complete loss of the membrane cytoskeletal protein dystrophin and concomitant drastic reduction in dystrophin-associated glycoproteins are the underlying mechanisms of the highly progressive neuromuscular disorder Duchenne muscular dystrophy. In order to identify new potential binding partners of dystrophin or proteins in close proximity to the sarcolemmal dystrophin complex, proteomic profiling of the isolated dystrophin-glycoprotein complex was carried out. Subcellular membrane fractionation and detergent solubilisation, in combination with ion exchange, lectin chromatography and density gradient ultracentrifugation, was performed to isolate a dystrophin complex-enriched fraction. Following gradient gel electrophoresis and on-membrane digestion, the protein constituents of the dystrophin fraction were determined by peptide mass spectrometry. This proteomic strategy resulted in the novel identification of desmoglein and desmoplakin, which act as cytolinker proteins and possibly exist in close proximity to the dystrophin complex in the sarcolemma membrane. Interestingly, comparative immunoblotting showed a significant reduction in desmoglein in dystrophin-deficient mdx skeletal muscles, reminiscent of the pathobiochemical fate of the dystrophin-associated core proteins in muscular dystrophy. Comparative membrane proteomics was used to correlate this novel finding to large-scale changes in the dystrophic phenotype. A drastic increase in the extracellular stabilizers biglycan and fibronectin was shown by both mass spectrometric analysis and immunoblotting. The reduced expression of desmoglein in dystrophin-deficient skeletal muscles, and simultaneous increase in components of the extracellular matrix, suggest that muscular dystrophy is associated with plasmalemmal disintegration, loss of cellular linkage and reactive myofibrosis.

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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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Treatment with human immunoglobulin G improves the early disease course in a mouse model of Duchenne muscular dystrophy

Cited by 17 publications

References 54 publications

Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

Proteomic profiling of the dystrophin complex and membrane fraction from dystrophic mdx muscle reveals decreases in the cytolinker desmoglein and increases in the extracellular matrix stabilizers biglycan and fibronectin

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

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