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

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

Metabolites ◽

10.3390/metabo8040061 ◽

2018 ◽

Vol 8 (4) ◽

pp. 61 ◽

Cited By ~ 10

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.

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Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

Molecular Therapy ◽

10.1016/j.ymthe.2019.12.011 ◽

2020 ◽

Vol 28 (3) ◽

pp. 845-854 ◽

Cited By ~ 2

Author(s):

Nalinda B. Wasala ◽

Yongping Yue ◽

William Lostal ◽

Lakmini P. Wasala ◽

Nandita Niranjan ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Dilated Cardiomyopathy

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Reversal of cardiac and skeletal manifestations of Duchenne muscular dystrophy by cardiosphere-derived cells and their exosomes in mdx dystrophic mice and in human Duchenne cardiomyocytes

10.1101/128900 ◽

2017 ◽

Cited By ~ 4

Author(s):

Mark A. Aminzadeh ◽

Russell G. Rogers ◽

Kenneth Gouin ◽

Mario Fournier ◽

Rachel E. Tobin ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Cardiac Function ◽

Premature Death ◽

Next Generation ◽

Skeletal Myopathy ◽

Genetic Deficiency ◽

Dystrophic Mice

Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy, affecting the heart as well as skeletal muscle. Here we report that cardiosphere-derived cells (CDCs), which are being tested clinically for the treatment of Duchenne cardiomyopathy, improve cardiac and skeletal myopathy in the mdx mouse model of DMD and in human Duchenne cardiomyocytes. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human Duchenne cardiomyocytes. The findings further motivate the testing of CDCs in Duchenne patients, while identifying exosomes as next-generation therapeutic candidates.

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Abstract 44: Telomere and Mitochondrial Dysfunction in Duchenne Muscular Dystrophy

Circulation Research ◽

10.1161/res.117.suppl_1.44 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Alex C Chang ◽

Sang-Ging Ong ◽

Joseph Wu ◽

Helen M Blau

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Dilated Cardiomyopathy ◽

Mitochondrial Dysfunction ◽

Telomere Length ◽

Dystrophin Gene ◽

Glycoprotein Complex ◽

The Difference

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disease that is result of mutations in the dystrophin gene and is the most common myopathic disease in humans with a prevalence of one in every 3500 males. Dystrophin is crucial for the formation of a dystrophin-glycoprotein complex (DGC), which connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix in both skeletal and cardiac muscles. In the heart, loss of dystrophin leads to increased fibrosis and death in the third decade of life due to dilated cardiomyopathy. A conundrum in studying and developing therapies for DMD has been the lack of a mouse model that fully recapitulates the clinical phenotype, as mice that lack dystrophin (mdx model), unlike patients, exhibit only mild skeletal muscle defects, essentially no cardiac defects and have a relatively normal lifespan. Our lab reasoned that the difference in the manifestation of the disease in mice and humans could be telomere length, as mice have substantially longer telomeres than humans. We created a novel mouse model with shortened telomere lengths (similar to humans) that fully recapitulates the skeletal muscle (Cell. 2010;143:1059-1071; the mdx/mTRKO model) and cardiac muscle phenotype of DMD (Nat Cell Biol. 2013; 15:895-904; dilated cardiomyopathy). Interestingly, we observed a relative 45% reduction in cardiomyocyte telomere length in our mdx/mTRKO animals (3 animals per group, N = 300-400) as well as patient samples (4 DMD patient samples, N = 40-95). Here we present new evidence of mitochondrial dysfunction and telomere dysfunction.

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

International Journal of Molecular Sciences ◽

10.3390/ijms23020958 ◽

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.

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Osteopontin (OPN) Downregulatory Alkaloid (-)-Agelastatin A Prevents Muscle Damage in a Mouse Model of Duchenne Muscular Dystrophy

10.26434/chemrxiv.14210882.v1 ◽

2021 ◽

Author(s):

Madison Feng ◽

Sara Mata Lopez ◽

Soraya Manaviazar ◽

Hamish A. Watson ◽

Karl Hale ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Animal Models ◽

Mouse Model ◽

Muscle Damage ◽

Mdx Mice ◽

Agelastatin A ◽

Dose Dependent Decrease ◽

Exercise Induced ◽

Dose Dependent

<p>(-)-Agelastatin A (AA) in 1,2-propanediol (3-deoxy-DL-glycerol) elicits a dose-dependent decrease in OPN mRNA expression in canine Duchenne Muscular Dystrophy (DMD) myoblasts at doses ranging from 0.01 nM-30 nM. When intraperitoneally administered in the same vehicle to mdx mice at 2.5 mg/kg/day for two weeks, and at 1.5 mg/kg/day twice-weekly for two weeks, (-)-AA brings about a significant decrease in exercise-induced muscle damage through its attenuation of OPN expression. Because (-)-AA is known to downregulate OPN, this study confirms that the use of small molecule OPN downregulatory drugs can beneficially modify the phenotype in DMD animal models and potentially affected boys</p>

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Dysregulated Autophagy and Mitophagy in a Mouse Model of Duchenne Muscular Dystrophy Remain Unchanged Following Heme Oxygenase-1 Knockout

International Journal of Molecular Sciences ◽

10.3390/ijms23010470 ◽

2021 ◽

Vol 23 (1) ◽

pp. 470

Author(s):

Olga Mucha ◽

Katarzyna Kaziród ◽

Paulina Podkalicka ◽

Kinga Rusin ◽

Józef Dulak ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Heme Oxygenase ◽

Mrna Level ◽

Mdx Mice ◽

Heme Oxygenase 1 ◽

Protein Levels ◽

Dystrophic Mice

Dysregulation of autophagy may contribute to the progression of various muscle diseases, including Duchenne muscular dystrophy (DMD). Heme oxygenase-1 (HO-1, encoded by Hmox1), a heme-degrading enzyme, may alleviate symptoms of DMD, inter alia, through anti-inflammatory properties. In the present study, we determined the role of HO-1 in the regulation of autophagy and mitophagy in mdx animals, a commonly used mouse model of the disease. In the gastrocnemius of 6-week-old DMD mice, the mRNA level of mitophagy markers: Bnip3 and Pink1, as well as autophagy regulators, e.g., Becn1, Map1lc3b, Sqstm1, and Atg7, was decreased. In the dystrophic diaphragm, changes in the latter were less prominent. In older, 12-week-old dystrophic mice, diminished expressions of Pink1 and Sqstm1 with upregulation of Atg5, Atg7, and Lamp1 was depicted. Interestingly, we demonstrated higher protein levels of autophagy regulator, LC3, in dystrophic muscles. Although the lack of Hmox1 in mdx mice influenced blood cell count and the abundance of profibrotic proteins, no striking differences in mRNA and protein levels of autophagy and mitophagy markers were found. In conclusion, we demonstrated complex, tissue, and age-dependent dysregulation of mitophagic and autophagic markers in DMD mice, which are not affected by the additional lack of Hmox1.

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Implications for Cardiac Function Following Rescue of the Dystrophic Diaphragm in a Mouse Model of Duchenne Muscular Dystrophy

Scientific Reports ◽

10.1038/srep11632 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 7

Author(s):

Corinne A. Betts ◽

Amer F. Saleh ◽

Carolyn A. Carr ◽

Sofia Muses ◽

Kim E. Wells ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Cardiac Function

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Humanizing the mdx mouse model of DMD: the long and the short of it

npj Regenerative Medicine ◽

10.1038/s41536-018-0045-4 ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 31

Author(s):

Nora Yucel ◽

Alex C. Chang ◽

John W. Day ◽

Nadia Rosenthal ◽

Helen M. Blau

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Dilated Cardiomyopathy ◽

Mouse Models ◽

Cardiac Failure ◽

Specific Treatment ◽

Mdx Mouse ◽

Cardiorespiratory Failure ◽

The Third

AbstractDuchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation.

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