scholarly journals Lipocalin 2 Influences Bone and Muscle Phenotype in the MDX Mouse Model of Duchenne Muscular Dystrophy

2022 ◽  
Vol 23 (2) ◽  
pp. 958
Author(s):  
Marco Ponzetti ◽  
Argia Ucci ◽  
Antonio Maurizi ◽  
Luca Giacchi ◽  
Anna Teti ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Bone Loss ◽  
Mouse Model ◽  
Mononuclear Cells ◽  
Serum Levels ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Muscle Fibres ◽  
Lipocalin 2

Lipocalin 2 (Lcn2) is an adipokine involved in bone and energy metabolism. Its serum levels correlate with bone mechanical unloading and inflammation, two conditions representing hallmarks of Duchenne Muscular Dystrophy (DMD). Therefore, we investigated the role of Lcn2 in bone loss induced by muscle failure in the MDX mouse model of DMD. We found increased Lcn2 serum levels in MDX mice at 1, 3, 6, and 12 months of age. Consistently, Lcn2 mRNA was higher in MDX versus WT muscles. Immunohistochemistry showed Lcn2 expression in mononuclear cells between muscle fibres and in muscle fibres, thus confirming the gene expression results. We then ablated Lcn2 in MDX mice, breeding them with Lcn2−/− mice (MDXxLcn2−/−), resulting in a higher percentage of trabecular volume/total tissue volume compared to MDX mice, likely due to reduced bone resorption. Moreover, MDXxLcn2−/− mice presented with higher grip strength, increased intact muscle fibres, and reduced serum creatine kinase levels compared to MDX. Consistently, blocking Lcn2 by treating 2-month-old MDX mice with an anti-Lcn2 monoclonal antibody (Lcn2Ab) increased trabecular volume, while reducing osteoclast surface/bone surface compared to MDX mice treated with irrelevant IgG. Grip force was also increased, and diaphragm fibrosis was reduced by the Lcn2Ab. These results suggest that Lcn2 could be a possible therapeutic target to treat DMD-induced bone loss.

scholarly journals Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy

Metabolites ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 61 ◽  
Author(s):  
Josiane Joseph ◽  
Dong Cho ◽  
Jason Doles
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Progenitor Cell ◽  
Treatment Options ◽  
Cell Types ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Metabolic Alterations ◽  
Potential Contributor

Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD.

scholarly journals Functional and Molecular Effects of Arginine Butyrate and Prednisone on Muscle and Heart in the mdx Mouse Model of Duchenne Muscular Dystrophy

PLoS ONE ◽  
2010 ◽  
Vol 5 (6) ◽  
pp. e11220 ◽  
Author(s):  
Alfredo D. Guerron ◽  
Rashmi Rawat ◽  
Arpana Sali ◽  
Christopher F. Spurney ◽  
Emidio Pistilli ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Mdx Mouse ◽  
Molecular Effects ◽  
Arginine Butyrate

Mss51 deletion increases endurance and ameliorates histopathology in the mdx mouse model of Duchenne muscular dystrophy

2021 ◽  
Vol 35 (2) ◽  
Author(s):  
Yazmin I. Rovira Gonzalez ◽  
Adam L. Moyer ◽  
Nicolas J. LeTexier ◽  
August D. Bratti ◽  
Siyuan Feng ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Mdx Mouse

Talin, vinculin and DRP (utrophin) concentrations are increased at mdx myotendinous junctions following onset of necrosis

1994 ◽  
Vol 107 (6) ◽  
pp. 1477-1483 ◽  
Author(s):  
D.J. Law ◽  
D.L. Allen ◽  
J.G. Tidball
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cytoskeletal Proteins ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Myotendinous Junction ◽  
Glycoprotein Complex ◽  
Transmembrane Glycoprotein ◽  
Muscle Necrosis ◽  
Myotendinous Junctions

Duchenne muscular dystrophy (DMD) and the myopathy seen in the mdx mouse both result from absence of the protein dystrophin. Structural similarities between dystrophin and other cytoskeletal proteins, its enrichment at myotendinous junctions, and its indirect association with laminin mediated by a transmembrane glycoprotein complex suggest that one of dystrophin's functions in normal muscle is to form one of the links between the actin cytoskeleton and the extracellular matrix. Unlike Duchenne muscular dystrophy patients, mdx mice suffer only transient muscle necrosis, and are able to regenerate damaged muscle tissue. The present study tests the hypothesis that mdx mice partially compensate for dystrophin's absence by upregulating one or more dystrophin-independent mechanisms of cytoskeleton-membrane association. Quantitative analysis of immunoblots of adult mdx muscle samples showed an increase of approximately 200% for vinculin and talin, cytoskeletal proteins that mediate thin filament-membrane interactions at myotendinous junctions. Blots also showed an increase (143%) in the dystrophin-related protein called utrophin, another myotendinous junction constituent, which may be able to substitute for dystrophin directly. Muscle samples from 2-week-old animals, a period immediately preceding the onset of muscle necrosis, showed no significant differences in protein concentration between mdx and controls. Quantitative analyses of confocal images of myotendinous junctions from mdx and control muscles show significantly higher concentrations of talin and vinculin at the myotendinous junctions of mdx muscle. These findings indicate that mdx mice may compensate in part for the absence of dystrophin by increased expression of other molecules that subsume dystrophin's mechanical function.

Ifetroban Reduces Coronary Artery Dysfunction in a Mouse Model of Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Ray Mitchell ◽  
Norman E Frederick ◽  
Emily R Holzman ◽  
Francesca Agobe ◽  
Heather C M Allaway ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Coronary Arteries ◽  
Oral Treatment ◽  
Mdx Mice ◽  
Muscarinic Agonist ◽  
Therapeutic Implications

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne Muscular Dystrophy (DMD), an inheritable muscle wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A2/prostanoid receptor (TPr) antagonist, ifetroban. Further, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceutical) is currently recruiting subjects to determine if ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (~3-5 months) and aged (~9-12 months) mdx mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619(U4) was enhanced in young mdx mice versus controls. Additionally, young mdx mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mdx mice, U4-mediated vasoconstriction was measured in the absence and presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD.

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