Abstract 252: The Capsaicin Sensitive Afferent Neuron Innervating Skeletal Muscle is Abnormal in the Mdx Mouse

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Qinglu Li ◽  
Mary Garry
Keyword(s):  
Blood Pressure ◽  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Blood Pressure Response ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Afferent Neuron ◽  
Afferent Neurons ◽  
Left Common Iliac Artery

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy caused by a mutation of the dystrophin gene at locus Xp21, located on the short arm of the X chromosome. Muscle wasting and weakness are common in DMD and in the murine mdx model. We previously demonstrated Group III and IV afferent neurons, which innervate skeletal muscle and control blood pressure and heart rate in response to exercise, are abnormal in settings of ischemia and atrophy; such as cardiomyopathy. We hypothesized that these afferent neurons would also display abnormalities in the mdx mouse. To test this hypothesis, we developed a decerebrate mouse model using 10 wk and 6 mo old male BL10 WT and MDX mice to test mean arterial pressure (MAP) responses to intra-arterial capsaicin (IA-Cap; a specific stimulant of group IV afferent neurons). Mice were anesthetized and MAP was continuously recorded with a pressure transducer in the left carotid artery after which the animal was rendered decerebrate. Following decerebration, anesthesia was discontinued and IA-Cap (0,003-1ug/100ul) was delivered via the left common iliac artery. In rats, we have demonstrated this to be a valid model for evaluating MAP responses to activation of metabolically active afferent neurons. We observed that MAP increased in a dose-related fashion in both 10wk and 6 mo old WT and MDX, while 10 wk old MDX mouse had a normal response, the 6 months MDX mouse response was significantly blunted when compared to WT. To test whether these abnormalities are related to the onset of cardiomyopathy, Echocardiography was performed using 6 months old BL10 WT and MDX mice, no abnormality was found in terms of LV dimensions and function in MDX mice comparing with WT mice. Further studies will be performed to determine whether these abnormalities are inherent to changes in the skeletal muscle of the mdx mouse. We conclude that this murine model displays pressor responses to IA-Cap, similar to the rat and that MDX mice have a blunted blood pressure response to IA-Cap. These results indicate that abnormalities exist within the skeletal muscle afferent neurons in the mdx model.

scholarly journals Circadian Genes as Exploratory Biomarkers in DMD: Results From Both the mdx Mouse Model and Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Rachele Rossi ◽  
Maria Sofia Falzarano ◽  
Hana Osman ◽  
Annarita Armaroli ◽  
Chiara Scotton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Circadian Rhythm ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Expression Profiles ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Muscle Biopsies

Duchenne muscular dystrophy (DMD) is a rare genetic disease due to dystrophin gene mutations which cause progressive weakness and muscle wasting. Circadian rhythm coordinates biological processes with the 24-h cycle and it plays a key role in maintaining muscle functions, both in animal models and in humans. We explored expression profiles of circadian circuit master genes both in Duchenne muscular dystrophy skeletal muscle and in its animal model, the mdx mouse. We designed a customized, mouse-specific Fluidic-Card-TaqMan-based assay (Fluid-CIRC) containing thirty-two genes related to circadian rhythm and muscle regeneration and analyzed gastrocnemius and tibialis anterior muscles from both unexercised and exercised mdx mice. Based on this first analysis, we prioritized the 7 most deregulated genes in mdx mice and tested their expression in skeletal muscle biopsies from 10 Duchenne patients. We found that CSNK1E, SIRT1, and MYOG are upregulated in DMD patient biopsies, consistent with the mdx data. We also demonstrated that their proteins are detectable and measurable in the DMD patients’ plasma. We suggest that CSNK1E, SIRT1, and MYOG might represent exploratory circadian biomarkers in 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 Lmo7 is dispensable for skeletal muscle and cardiac function

2015 ◽  
Vol 309 (7) ◽  
pp. C470-C479 ◽  
Author(s):  
Dieu Hung Lao ◽  
Mary C. Esparza ◽  
Shannon N. Bremner ◽  
Indroneal Banerjee ◽  
Jianlin Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Cardiac Function ◽  
Cardiac Muscle ◽  
Mapk Pathway ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Mouse Line

Emery-Dreifuss muscular dystrophy (EDMD) is a degenerative disease primarily affecting skeletal muscles in early childhood as well as cardiac muscle at later stages. EDMD is caused by a number of mutations in genes encoding proteins associated with the nuclear envelope (e.g., Emerin, Lamin A/C, and Nesprin). Recently, a novel protein, Lim-domain only 7 ( lmo7) has been reported to play a role in the molecular pathogenesis of EDMD. Prior in vitro and in vivo studies suggested the intriguing possibility that Lmo7 plays a role in skeletal or cardiac muscle pathophysiology. To further understand the in vivo role of Lmo7 in striated muscles, we generated a novel Lmo7-null ( lmo7−/−) mouse line. Using this mouse line, we examined skeletal and cardiac muscle physiology, as well as the role of Lmo7 in a model of muscular dystrophy and regeneration using the dystrophin-deficient mdx mouse model. Our results demonstrated that lmo7−/− mice had no abnormalities in skeletal muscle morphology, physiological function, or regeneration. Cardiac function was also unaffected. Moreover, we found that ablation of lmo7 in mdx mice had no effect on the observed myopathy and muscular regeneration exhibited by mdx mice. Molecular analyses also showed no changes in dystrophin complex factors, MAPK pathway components, and Emerin levels in lmo7 knockout mice. Taken together, we conclude that Lmo7 is dispensable for skeletal muscle and cardiac physiology and pathophysiology.

scholarly journals Profiling of Age-Related Changes in theTibialis AnteriorMuscle Proteome of the mdx Mouse Model of Dystrophinopathy

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Steven Carberry ◽  
Margit Zweyer ◽  
Dieter Swandulla ◽  
Kay Ohlendieck
Keyword(s):  
Muscular Dystrophy ◽  
Tibialis Anterior ◽  
Large Scale ◽  
Small Heat Shock Protein ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Global Changes ◽  
Altered Expression ◽  
Age Related

X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdxtibialis anteriormuscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdxtibialis anteriormuscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy.

Pax7, Pax3 and Mamstr genes are involved in skeletal muscle impaired regeneration of dy2J/dy2J mouse model of Lama2-CMD

2019 ◽  
Vol 28 (20) ◽  
pp. 3369-3390 ◽  
Author(s):  
Nurit Yanay ◽  
Moran Elbaz ◽  
Jenya Konikov-Rozenman ◽  
Sharona Elgavish ◽  
Yuval Nevo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Pathway Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Congenital Muscular Dystrophy ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Rna Seq ◽  
Mesenchymal Transition

Abstract Congenital muscular dystrophy type-1A (Lama2-CMD) and Duchenne muscular dystrophy (DMD) result from deficiencies of laminin-α2 and dystrophin proteins, respectively. Although both proteins strengthen the sarcolemma, they are implicated in clinically distinct phenotypes. We used RNA-deep sequencing (RNA-Seq) of dy2J/dy2J, Lama2-CMD mouse model, skeletal muscle at 8 weeks of age to elucidate disease pathophysiology. This study is the first report of dy2J/dy2J model whole transcriptome profile. RNA-Seq of the mdx mouse model of DMD and wild-type (WT) mouse was carried as well in order to enable a novel comparison of dy2J/dy2J to mdx. A large group of shared differentially expressed genes (DEGs) was found in dy2J/dy2J and mdx models (1834 common DEGs, false discovery rate [FDR] < 0.05). Enrichment pathway analysis using ingenuity pathway analysis showed enrichment of inflammation, fibrosis, cellular movement, migration and proliferation of cells, apoptosis and necrosis in both mouse models (P-values 3E-10–9E-37). Via canonical pathway analysis, actin cytoskeleton, integrin, integrin-linked kinase, NF-kB, renin–angiotensin, epithelial–mesenchymal transition, and calcium signaling were also enriched and upregulated in both models (FDR < 0.05). Interestingly, significant downregulation of Pax7 was detected in dy2J/dy2J compared to upregulation of this key regeneration gene in mdx mice. Pax3 and Mamstr genes were also downregulated in dy2J/dy2J compared to WT mice. These results may explain the distinct disease course and severity in these models. While the mdx model at that stage shows massive regeneration, the dy2J/dy2J shows progressive dystrophic process. Our data deepen our understanding of the molecular pathophysiology and suggest new targets for additional therapies to upregulate regeneration in Lama2-CMD.

Branched fibers in dystrophic mdx muscle are associated with a loss of force following lengthening contractions

2007 ◽  
Vol 293 (3) ◽  
pp. C985-C992 ◽  
Author(s):  
S. Chan ◽  
S. I. Head ◽  
J. W. Morley
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Extensor Digitorum Longus ◽  
Muscle Fibers ◽  
Force Production ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Dystrophic Muscle ◽  
Lengthening Contractions ◽  
Fast Twitch

We demonstrated that the susceptibility of skeletal muscle to injury from lengthening contractions in the dystrophin-deficient mdx mouse is directly linked with the extent of fiber branching within the muscles and that both parameters increase as the mdx animal ages. We subjected isolated extensor digitorum longus muscles to a lengthening contraction protocol of 15% strain and measured the resulting drop in force production (force deficit). We also examined the morphology of individual muscle fibers. In mdx mice 1–2 mo of age, 17% of muscle fibers were branched, and the force deficit of 7% was not significantly different from that of age-matched littermate controls. In mdx mice 6–7 mo of age, 89% of muscle fibers were branched, and the force deficit of 58% was significantly higher than the 25% force deficit of age-matched littermate controls. These data demonstrated an association between the extent of branching and the greater vulnerability to contraction-induced injury in the older fast-twitch dystrophic muscle. Our findings demonstrate that fiber branching may play a role in the pathogenesis of muscular dystrophy in mdx mice, and this could affect the interpretation of previous studies involving lengthening contractions in this animal.

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

2002 ◽  
Vol 283 (3) ◽  
pp. C773-C784 ◽  
Author(s):  
Karl Rouger ◽  
Martine Le Cunff ◽  
Marja Steenman ◽  
Marie-Claude Potier ◽  
Nathalie Gibelin ◽  
...  
Keyword(s):  
Dystrophin Gene ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
First Year ◽  
Temporal Gene Expression ◽  
Cell Functions ◽  
Hindlimb Muscles ◽  
Genes Encoding ◽  
Dystrophin Protein

The mdx mouse is a model for human Duchenne muscular dystrophy (DMD), an X-linked degenerative disease of skeletal muscle tissue characterized by the absence of the dystrophin protein. The mdx mice display a much milder phenotype than DMD patients. After the first week of life when all mdx muscles evolve like muscles of young DMD patients, mdx hindlimb muscles substantially compensate for the lack of dystrophin, whereas mdx diaphragm muscle becomes progressively affected by the disease. We used cDNA microarrays to compare the expression profile of 1,082 genes, previously selected by a subtractive method, in control and mdx hindlimb and diaphragm muscles at 12 time points over the first year of the mouse life. We determined that 1) the dystrophin gene defect induced marked expression remodeling of 112 genes encoding proteins implicated in diverse muscle cell functions and 2) two-thirds of the observed transcriptomal anomalies differed between adult mdx hindlimb and diaphragm muscles. Our results showed that neither mdx diaphram muscle nor mdx hindlimb muscles evolve entirely like the human DMD muscles. This finding should be taken under consideration for the interpretation of future experiments using mdx mice as a model for therapeutic assays.

scholarly journals Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1

2009 ◽  
Vol 20 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Michelle S. Steen ◽  
Marvin E. Adams ◽  
Yan Tesch ◽  
Stanley C. Froehner
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Mdx Mouse ◽  
Lysosomal Storage ◽  
Transgenic Expression ◽  
New Therapeutic Approaches ◽  
Human Disorders ◽  
Niemann Pick ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.

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.

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.

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