scholarly journals Improvement of Endurance of DMD Animal Model Using Natural Polyphenols

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Clementina Sitzia ◽  
Andrea Farini ◽  
Federica Colleoni ◽  
Francesco Fortunato ◽  
Paola Razini ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Genetic Defect ◽  
Premature Death ◽  
Mdx Mice ◽  
Dystrophic Muscle ◽  
Muscle Fibrosis ◽  
Natural Polyphenols ◽  
Dystrophin Deficiency ◽  
Force Reduction ◽  
Muscular Architecture

Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy, is characterized by muscular wasting caused by dystrophin deficiency that ultimately ends in force reduction and premature death. In addition to primary genetic defect, several mechanisms contribute to DMD pathogenesis. Recently, antioxidant supplementation was shown to be effective in the treatment of multiple diseases including muscular dystrophy. Different mechanisms were hypothesized such as reduced hydroxyl radicals, nuclear factor-κB deactivation, and NO protection from inactivation. Following these promising evidences, we investigated the effect of the administration of a mix of dietary natural polyphenols (ProAbe) on dystrophic mdx mice in terms of muscular architecture and functionality. We observed a reduction of muscle fibrosis deposition and myofiber necrosis together with an amelioration of vascularization. More importantly, the recovery of the morphological features of dystrophic muscle leads to an improvement of the endurance of treated dystrophic mice. Our data confirmed that ProAbe-based diet may represent a strategy to coadjuvate the treatment of DMD.

scholarly journals Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

2019 ◽  
Vol 8 ◽  
pp. 204800401987958
Author(s):  
HR Spaulding ◽  
C Ballmann ◽  
JC Quindry ◽  
MB Hudson ◽  
JT Selsby
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Dystrophin Deficiency ◽  
Muscle Wasting Disease ◽  
Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

scholarly journals Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy

2021 ◽  
Vol 22 (13) ◽  
pp. 7063
Author(s):  
Sharon Mordechay ◽  
Shaun Smullen ◽  
Paul Evans ◽  
Olga Genin ◽  
Mark Pines ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Motor Coordination ◽  
Mdx Mice ◽  
Cell Viability Assay ◽  
Muscle Fibrosis ◽  
Antifibrotic Therapy ◽  
Racemic Form ◽  
Viability Assay

Progressive loss of muscle and muscle function is associated with significant fibrosis in Duchenne muscular dystrophy (DMD) patients. Halofuginone, an analog of febrifugine, prevents fibrosis in various animal models, including those of muscular dystrophies. Effects of (+)/(−)-halofuginone enantiomers on motor coordination and diaphragm histopathology in mdx mice, the mouse model for DMD, were examined. Four-week-old male mice were treated with racemic halofuginone, or its separate enantiomers, for 10 weeks. Controls were treated with saline. Racemic halofuginone-treated mice demonstrated better motor coordination and balance than controls. However, (+)-halofuginone surpassed the racemic form’s effect. No effect was observed for (−)-halofuginone, which behaved like the control. A significant reduction in collagen content and degenerative areas, and an increase in utrophin levels were observed in diaphragms of mice treated with racemic halofuginone. Again, (+)-halofuginone was more effective than the racemic form, whereas (−)-halofuginone had no effect. Both racemic and (+)-halofuginone increased diaphragm myofiber diameters, with no effect for (−)-halofuginone. No effects were observed for any of the compounds tested in an in-vitro cell viability assay. These results, demonstrating a differential effect of the halofuginone enantiomers and superiority of (+)-halofuginone, are of great importance for future use of (+)-halofuginone as a DMD antifibrotic therapy.

scholarly journals Laminin-111 protein therapy enhances muscle regeneration and repair in the GRMD dog model of Duchenne muscular dystrophy

2019 ◽  
Vol 28 (16) ◽  
pp. 2686-2695 ◽  
Author(s):  
Pamela Barraza-Flores ◽  
Tatiana M Fontelonga ◽  
Ryan D Wuebbles ◽  
Hailey J Hermann ◽  
Andreia M Nunes ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Premature Death ◽  
Muscle Disease ◽  
Muscle Pathology ◽  
Mdx Mouse ◽  
Protein Therapy ◽  
Muscle Fibrosis ◽  
Dog Model

Abstract Duchenne muscular dystrophy (DMD) is a devastating X-linked disease affecting ~1 in 5000 males. DMD patients exhibit progressive muscle degeneration and weakness, leading to loss of ambulation and premature death from cardiopulmonary failure. We previously reported that mouse Laminin-111 (msLam-111) protein could reduce muscle pathology and improve muscle function in the mdx mouse model for DMD. In this study, we examined the ability of msLam-111 to prevent muscle disease progression in the golden retriever muscular dystrophy (GRMD) dog model of DMD. The msLam-111 protein was injected into the cranial tibial muscle compartment of GRMD dogs and muscle strength and pathology were assessed. The results showed that msLam-111 treatment increased muscle fiber regeneration and repair with improved muscle strength and reduced muscle fibrosis in the GRMD model. Together, these findings support the idea that Laminin-111 could serve as a novel protein therapy for the treatment of DMD.

scholarly journals PAI-1–regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy

2012 ◽  
Vol 196 (1) ◽  
pp. 163-175 ◽  
Author(s):  
Esther Ardite ◽  
Eusebio Perdiguero ◽  
Berta Vidal ◽  
Susana Gutarra ◽  
Antonio L. Serrano ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Transforming Growth Factor ◽  
Proteolytic Processing ◽  
Mdx Mice ◽  
Muscle Fibrosis ◽  
Type Plasminogen Activator ◽  
Important Regulator ◽  
Muscle Homeostasis ◽  
Phosphatase And Tensin Homologue ◽  
Pai 1

Disruption of skeletal muscle homeostasis by substitution with fibrotic tissue constitutes the principal cause of death in Duchenne muscular dystrophy (DMD) patients, yet the implicated fibrogenic mechanisms remain poorly understood. This study identifies the extracellular PAI-1/urokinase-type plasminogen activator (uPA) balance as an important regulator of microribonucleic acid (miR)–21 biogenesis, controlling age-associated muscle fibrosis and dystrophy progression. Genetic loss of PAI-1 in mdx dystrophic mice anticipated muscle fibrosis through these sequential mechanisms: the alteration of collagen metabolism by uPA-mediated proteolytic processing of transforming growth factor (TGF)–β in muscle fibroblasts and the activation of miR-21 expression, which inhibited phosphatase and tensin homologue and enhanced AKT signaling, thus endowing TGF-β with a remarkable cell proliferation–promoting potential. Age-associated fibrogenesis and muscle deterioration in mdx mice, as well as exacerbated dystrophy in young PAI-1−/− mdx mice, could be reversed by miR-21 or uPA-selective interference, whereas forced miR-21 overexpression aggravated disease severity. The PAI-1–miR-21 fibrogenic axis also appeared dysregulated in muscle of DMD patients, providing a basis for effectively targeting fibrosis and muscular dystrophies in currently untreatable individuals.

scholarly journals Sulforaphane mitigates muscle fibrosis in mdx mice via Nrf2-mediated inhibition of TGF-β/Smad signaling

2016 ◽  
Vol 120 (4) ◽  
pp. 377-390 ◽  
Author(s):  
Chengcao Sun ◽  
Shujun Li ◽  
Dejia Li
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mdx Mice ◽  
Related Factor ◽  
Dependent Manner ◽  
Dystrophic Muscle ◽  
Smad Signaling ◽  
Muscle Fibrosis ◽  
Smad Signaling Pathway

Sulforaphane (SFN), an activator of NF-E2-related factor 2 (Nrf2), has been found to have an antifibrotic effect on liver and lung. However, its effects on dystrophic muscle fibrosis remain unknown. This work was undertaken to evaluate the effects of SFN-mediated activation of Nrf2 on dystrophic muscle fibrosis. Male mdx mice (age 3 mo) were treated with SFN by gavage (2 mg/kg body wt per day) for 3 mo. Experimental results demonstrated that SFN remarkably attenuated skeletal and cardiac muscle fibrosis as indicated by reduced Sirius Red staining and immunostaining of the extracellular matrix. Moreover, SFN significantly inhibited the transforming growth factor-β (TGF-β)/Smad signaling pathway and suppressed profibrogenic gene and protein expressions such as those of α-smooth muscle actin (α-SMA), fibronectin, collagen I, plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor metalloproteinase-1 (TIMP-1) in an Nrf2-dependent manner. Furthermore, SFN significantly decreased the expression of inflammatory cytokines CD45, TNF-α, and IL-6 in mdx mice. In conclusion, these results show that SFN can attenuate dystrophic muscle fibrosis by Nrf2-mediated inhibition of the TGF-β/Smad signaling pathway, which indicates that Nrf2 may represent a new target for dystrophic muscle fibrosis.

scholarly journals Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246507
Author(s):  
Michael Ziemba ◽  
Molly Barkhouse ◽  
Kitipong Uaesoontrachoon ◽  
Mamta Giri ◽  
Yetrib Hathout ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Serum Proteins ◽  
Mdx Mice ◽  
Proteomic Profiling ◽  
Treatment Groups ◽  
Dystrophin Deficiency ◽  
Repurposed Drugs ◽  
Good Concordance ◽  
Pharmacodynamic Biomarkers

Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFβ fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, β-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFβ cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.

Contractile function and low-intensity exercise effects of old dystrophic (mdx) mice

1998 ◽  
Vol 274 (4) ◽  
pp. C1138-C1144 ◽  
Author(s):  
Alan Hayes ◽  
David A. Williams
Keyword(s):  
Muscular Dystrophy ◽  
Contractile Function ◽  
Weight Bearing ◽  
Contractile Properties ◽  
Mdx Mice ◽  
Type I ◽  
Dystrophic Muscle ◽  
Low Intensity ◽  
Duchenne's Muscular Dystrophy ◽  
Low Intensity Exercise

Old mdx mice display a severe myopathy almost identical to Duchenne’s muscular dystrophy. This study examined the contractile properties of old mdxmuscles and investigated any effects of low-intensity exercise. Isometric contractile properties of the extensor digitorum longus (EDL) and soleus muscles were tested in adult (8–10 mo) and old (24 mo, split into sedentary and exercised groups) mdx mice. The EDL and soleus from old mdx mice exhibited decreased absolute twitch and tetanic forces, and the soleus exhibited a >50% decrease in relative forces (13.4 ± 0.4 vs. 6.0 ± 0.9 N/cm2) compared with adult mice. Old mdx muscles also showed longer contraction times and a higher percentage of type I fibers. Normal and mdx mice completed 10 wk of swimming, but mdx mice spent significantly less time swimming than normal animals (7.8 ± 0.4 vs. 15.8 ± 1.1 min, respectively). However, despite their severe dystrophy, mdx muscles responded positively to the low-intensity exercise. Relative tetanic tensions were increased (∼25% and ∼45% for the EDL and soleus, respectively) after the swimming, although absolute forces were unaffected. Thus these results indicate that, even with a dystrophin-deficient myopathy, mdx muscles can still respond to low-intensity exercise. This study shows that the contractile function of muscles of old mdx mice displays many similarities to that of human dystrophic patients and provides further evidence that the use of non-weight-bearing, low-intensity exercises, such as swimming, has no detrimental effect on dystrophic muscle and could be a useful therapeutic aid for sufferers of muscular dystrophy.

scholarly journals Desmin is a modifier of dystrophic muscle features in Mdx mice

2019 ◽  
Author(s):  
Arnaud Ferry ◽  
Julien Messéant ◽  
Ara Parlakian ◽  
Mégane Lemaitre ◽  
Pauline Roy ◽  
...  
Keyword(s):  
Neuromuscular Disease ◽  
Muscle Hypertrophy ◽  
Force Production ◽  
Muscle Performance ◽  
Mdx Mice ◽  
Force Transmission ◽  
Dystrophic Muscle ◽  
Adeno Associated Virus ◽  
Dystrophin Deficiency ◽  
Insight Into

AbstractDuchenne muscular dystrophy (DMD) is a severe neuromuscular disease, caused by dystrophin deficiency. Desmin is like dystrophin associated to costameric structures bridging sarcomeres to extracellular matrix that are involved in force transmission and skeletal muscle integrity. In the present study, we wanted to gain further insight into the roles of desmin which expression is increased in the muscle from the mouse Mdx DMD model. We show that a deletion of the desmin gene (Des) in Mdx mice (DKO, Mdx:desmin-/-) induces a marked worsening of the weakness (reduced maximal force production) as compared to Mdx mice. Fragility (higher susceptibility to contraction-induced injury) was also aggravated and fatigue resistance was reduced in DKO mice. Moreover, in contrast to Mdx mice, the DKO mice did not undergo a muscle hypertrophy because of smaller and less numerous fibers, with reduced percentage of centronucleated fibres. Interestingly, Desmin cDNA transfer with adeno-associated virus in 1-month-old DKO mice and newborn Mdx mice improved muscle weakness. Overall, desmin plays important and beneficial roles on muscle performance, fragility and remodelling in dystrophic Mdx mice.

scholarly journals Evidence for impaired neurovascular transmission in a murine model of Duchenne muscular dystrophy

2011 ◽  
Vol 110 (3) ◽  
pp. 601-609 ◽  
Author(s):  
Pooneh Bagher ◽  
Dongsheng Duan ◽  
Steven S. Segal
Keyword(s):  
Blood Flow ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Nerve Stimulation ◽  
Murine Model ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Response Curves ◽  
Dystrophic Muscle ◽  
Neurovascular Transmission

Duchenne muscular dystrophy (DMD) is a muscle-wasting disease caused by mutations in the dystrophin gene. Little is known about how blood flow control is affected in arteriolar networks supplying dystrophic muscle. We tested the hypothesis that mdx mice, a murine model for DMD, exhibit defects in arteriolar vasomotor control. The cremaster muscle was prepared for intravital microscopy in pentobarbital sodium-anesthetized mdx and C57BL/10 control mice ( n ≥ 5 per group). Spontaneous vasomotor tone increased similarly with arteriolar branch order in both mdx and C57BL/10 mice [pooled values: first order (1A), 6%; second order (2A), 56%; and third order (3A), 61%] with no difference in maximal diameters between groups measured during equilibration with topical 10 μM sodium nitroprusside (pooled values: 1A, 70 ± 3 μm; 2A, 31 ± 3 μm; and 3A, 19 ± 3 μm). Concentration-response curves to acetylcholine (ACh) and norepinephrine added to the superfusion solution did not differ between mdx and C57BL/10 mice, nor did constriction to elevated (21%) oxygen. In response to local stimulation from a micropipette, conducted vasodilation to ACh and conducted vasoconstriction to KCl were also not different between groups; however, constriction decayed with distance ( P < 0.05) whereas dilation did not. Remarkably, arteriolar constriction to perivascular nerve stimulation (PNS) at 2, 4, and 8 Hz was reduced by ∼25–30% in mdx mice compared with C57BL/10 mice ( P < 0.05). With intact arteriolar reactivity to agonists, attenuated constriction to perivascular nerve stimulation indicates impaired neurovascular transmission in arterioles controlling blood flow in mdx mice.

scholarly journals A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice

2001 ◽  
Vol 155 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Michelle Wehling ◽  
Melissa J. Spencer ◽  
James G. Tidball
Keyword(s):  
Nitric Oxide ◽  
Muscular Dystrophy ◽  
Nitric Oxide Synthase ◽  
Muscle Membrane ◽  
Mdx Mice ◽  
No Production ◽  
Dystrophic Muscle ◽  
Membrane Injury ◽  
Oxide Synthase

Dystrophin-deficient muscles experience large reductions in expression of nitric oxide synthase (NOS), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, we propose that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented the majority of muscle membrane injury that is detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. Furthermore, our data show that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. Finally, our data show that antibody depletions of macrophages from mdx mice cause significant reductions in muscle membrane injury. Together, these findings indicate that macrophages promote injury of dystrophin-deficient muscle, and the loss of normal levels of NO production by dystrophic muscle exacerbates inflammation and membrane injury in muscular dystrophy.

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