Journal articles: 'Muscular dystrophic x-linked (mdx)'

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Nogami, Ken'ichiro, Yusuke Maruyama, Fusako Sakai-Takemura, Norio Motohashi, Ahmed Elhussieny, Michihiro Imamura, Satoshi Miyashita, et al. "Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice." Human Molecular Genetics 30, no. 11 (April 5, 2021): 1006–19. http://dx.doi.org/10.1093/hmg/ddab100.

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Abstract Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.

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Carberry, Steven, Margit Zweyer, Dieter Swandulla, and Kay Ohlendieck. "Profiling of Age-Related Changes in theTibialis AnteriorMuscle Proteome of the mdx Mouse Model of Dystrophinopathy." Journal of Biomedicine and Biotechnology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/691641.

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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.

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Cui, Chang-Hao, Taro Uyama, Kenji Miyado, Masanori Terai, Satoru Kyo, Tohru Kiyono, and Akihiro Umezawa. "Menstrual Blood-derived Cells Confer Human Dystrophin Expression in the Murine Model of Duchenne Muscular Dystrophy via Cell Fusion and Myogenic Transdifferentiation." Molecular Biology of the Cell 18, no. 5 (May 2007): 1586–94. http://dx.doi.org/10.1091/mbc.e06-09-0872.

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Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder in children, is an X-linked recessive muscle disease characterized by the absence of dystrophin at the sarcolemma of muscle fibers. We examined a putative endometrial progenitor obtained from endometrial tissue samples to determine whether these cells repair muscular degeneration in a murine mdx model of DMD. Implanted cells conferred human dystrophin in degenerated muscle of immunodeficient mdx mice. We then examined menstrual blood–derived cells to determine whether primarily cultured nontransformed cells also repair dystrophied muscle. In vivo transfer of menstrual blood–derived cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of dystrophin. Labeling of implanted cells with enhanced green fluorescent protein and differential staining of human and murine nuclei suggest that human dystrophin expression is due to cell fusion between host myocytes and implanted cells. In vitro analysis revealed that endometrial progenitor cells and menstrual blood–derived cells can efficiently transdifferentiate into myoblasts/myocytes, fuse to C2C12 murine myoblasts by in vitro coculturing, and start to express dystrophin after fusion. These results demonstrate that the endometrial progenitor cells and menstrual blood–derived cells can transfer dystrophin into dystrophied myocytes through cell fusion and transdifferentiation in vitro and in vivo.

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Pelosi, Laura, Laura Forcina, Carmine Nicoletti, Bianca Maria Scicchitano, and Antonio Musarò. "Increased Circulating Levels of Interleukin-6 Induce Perturbation in Redox-Regulated Signaling Cascades in Muscle of Dystrophic Mice." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/1987218.

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Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy.

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Lewis, Caroline, Harald Jockusch, and Kay Ohlendieck. "Proteomic Profiling of the Dystrophin-Deficient MDX Heart Reveals Drastically Altered Levels of Key Metabolic and Contractile Proteins." Journal of Biomedicine and Biotechnology 2010 (2010): 1–20. http://dx.doi.org/10.1155/2010/648501.

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Although Duchenne muscular dystrophy is primarily classified as a neuromuscular disease, cardiac complications play an important role in the course of this X-linked inherited disorder. The pathobiochemical steps causing a progressive decline in the dystrophic heart are not well understood. We therefore carried out a fluorescence difference in-gel electrophoretic analysis of 9-month-old dystrophin-deficient versus age-matched normal heart, using the established MDX mouse model of muscular dystrophy-related cardiomyopathy. Out of 2,509 detectable protein spots, 79 2D-spots showed a drastic differential expression pattern, with the concentration of 3 proteins being increased, including nucleoside diphosphate kinase and lamin-A/C, and of 26 protein species being decreased, including ATP synthase, fatty acid binding-protein, isocitrate dehydrogenase, NADH dehydrogenase, porin, peroxiredoxin, adenylate kinase, tropomyosin, actin, and myosin light chains. Hence, the lack of cardiac dystrophin appears to trigger a generally perturbed protein expression pattern in the MDX heart, affecting especially energy metabolism and contractile proteins.

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Culligan, Kevin, Niamh Banville, Paul Dowling, and Kay Ohlendieck. "Drastic reduction of calsequestrin-like proteins and impaired calcium binding in dystrophic mdx muscle." Journal of Applied Physiology 92, no. 2 (February 1, 2002): 435–45. http://dx.doi.org/10.1152/japplphysiol.00903.2001.

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Although the reduction in dystrophin-associated glycoproteins is the primary pathophysiological consequence of the deficiency in dystrophin, little is known about the secondary abnormalities leading to x-linked muscular dystrophy. As abnormal Ca2+ handling may be involved in myonecrosis, we investigated the fate of key Ca2+ regulatory membrane proteins in dystrophic mdx skeletal muscle membranes. Whereas the expression of the ryanodine receptor, the dihydropyridine receptor, the Ca2+-ATPase, and calsequestrin was not affected, a drastic decline in calsequestrin-like proteins of 150–220 kDa was observed in dystrophic microsomes using one-dimensional immunoblotting, two-dimensional immunoblotting with isoelectric focusing, diagonal two-dimensional blotting technique, and immunoprecipitation. In analogy, overall Ca2+ binding was reduced in the sarcoplasmic reticulum of dystrophic muscle. The reduction in Ca2+ binding proteins might be directly involved in triggering impaired Ca2+ sequestration within the lumen of the sarcoplasmic reticulum. Thus disturbed sarcolemmal Ca2+ fluxes seem to influence overall Ca2+homeostasis, resulting in distinct changes in the expression profile of a subset of Ca2+ handling proteins, which might be an important factor in the progressive functional decline of dystrophic muscle fibers.

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Wells, Dominic J., Aurora Ferrer, and Kim E. Wells. "Immunological hurdles in the path to gene therapy for Duchenne muscular dystrophy." Expert Reviews in Molecular Medicine 4, no. 23 (November 4, 2002): 1–23. http://dx.doi.org/10.1017/s146239940200515x.

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Patients with Duchenne muscular dystrophy (DMD), an X-linked lethal muscle-wasting disease, have abnormal expression of the protein dystrophin within their muscle fibres. In the mdx mouse model of this condition, both germline and neonatal somatic gene transfers of dystrophin cDNAs have demonstrated the potential of gene therapy in treating DMD. However, in many DMD patients, there appears to be no dystrophin expression when muscle biopsies are immunostained or western blots are performed. This raises the possibility that the expression of dystrophin following gene transfer might trigger a destructive immune response against this ‘neoantigen’. Immune responses can also be generated against the gene transfer vector used to transfect the dystrophic muscle, and the combined immune response could further damage the already inflamed muscle. These problems are now beginning to be investigated in immunocompetent mdx mice. Although much work remains to be done, there are promising indications that these immune responses might not prove as much of a concern as originally envisaged.

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Joseph, Josiane, Dong Cho, and Jason Doles. "Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy." Metabolites 8, no. 4 (October 3, 2018): 61. http://dx.doi.org/10.3390/metabo8040061.

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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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Schertzer, Jonathan D., Chris van der Poel, Thea Shavlakadze, Miranda D. Grounds, and Gordon S. Lynch. "Muscle-specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice." American Journal of Physiology-Cell Physiology 294, no. 1 (January 2008): C161—C168. http://dx.doi.org/10.1152/ajpcell.00399.2007.

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Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by the absence of functional dystrophin. Abnormal excitation-contraction (E-C) coupling has been reported in dystrophic muscle fibers from mdx mice, and alterations in E-C coupling components may occur as a direct result of dystrophin deficiency. We hypothesized that muscle-specific overexpression of insulin-growth factor-1 (IGF-I) would reduce E-C coupling failure in mdx muscle. Mechanically skinned extensor digitorum longus muscle fibers from mdx mice displayed a faster decline in depolarization-induced force responses (DIFR); however, there were no differences in sarcoplasmic reticulum (SR)-mediated Ca2+ resequestration or in the properties of the contractile apparatus when compared with nondystrophic controls. The rate of DIFR decline was restored to control levels in fibers from transgenic mdx mice that overexpressed IGF-I in skeletal muscle ( mdx/IGF-I mice). Dystrophic muscles have a lower transcript level of a specific dihydropyridine receptor (DHPR) isoform, and IGF-I-mediated changes in E-C coupling were associated with increased transcript levels of specific DHPR isoforms involved in Ca2+ regulation. Importantly, IGF-I overexpression also increased the sensitivity of the contractile apparatus to Ca2+. The results demonstrate that IGF-I can ameliorate fundamental aspects of E-C coupling failure in dystrophic muscle fibers and that these effects are important for the improvements in cellular function induced by this growth factor.

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Petrof, B. J., H. H. Stedman, J. B. Shrager, J. Eby, H. L. Sweeney, and A. M. Kelly. "Adaptations in myosin heavy chain expression and contractile function in dystrophic mouse diaphragm." American Journal of Physiology-Cell Physiology 265, no. 3 (September 1, 1993): C834—C841. http://dx.doi.org/10.1152/ajpcell.1993.265.3.c834.

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The X chromosome-linked muscular dystrophic (mdx) mouse lacks the subsarcolemmal protein dystrophin and thus represents a genetic homologue of human Duchenne muscular dystrophy. The present study examined alterations in diaphragm contractile properties and myosin heavy chain (MHC) expression in young (3-4 mo) and old (22-24 mo) control and mdx mice. In young mdx mice, maximum isometric tension (Po) was reduced to 50% of control values. An increase in fibers coexpressing types I (slow) and IIa MHC as well as regenerating fibers expressing embryonic MHC occurred, whereas IIx/b fibers were decreased. In the old mdx group, Po underwent a further reduction to 25% of control, and there was a slowing of twitch kinetics along with markedly increased diaphragm endurance. These changes were associated with an approximate sevenfold increase in type I MHC fibers and virtual elimination of the IIx/b fiber population; there was no detectable embryonic MHC expression. We conclude that the mdx diaphragm responds to progressive muscle degeneration with transition to a slower phenotype associated with reduced power output and augmented muscle endurance. In the setting of progressive muscle fiber destruction, these changes may help preserve contractile function and promote greater survival of remaining muscle fibers by decreasing cellular energy requirements.

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DOWLING, Paul, Philip DORAN, and Kay OHLENDIECK. "Drastic reduction of sarcalumenin in Dp427 (dystrophin of 427 kDa)-deficient fibres indicates that abnormal calcium handling plays a key role in muscular dystrophy." Biochemical Journal 379, no. 2 (April 15, 2004): 479–88. http://dx.doi.org/10.1042/bj20031311.

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Although the primary abnormality in dystrophin is the underlying cause for mdx (X-chromosome-linked muscular dystrophy), abnormal Ca2+ handling after sarcolemmal microrupturing appears to be the pathophysiological mechanism leading to muscle weakness. To develop novel pharmacological strategies for eliminating Ca2+-dependent proteolysis, it is crucial to determine the fate of Ca2+-handling proteins in dystrophin-deficient fibres. In the present study, we show that a key luminal Ca2+-binding protein SAR (sarcalumenin) is affected in mdx skeletal-muscle fibres. One- and two-dimensional immunoblot analyses revealed the relative expression of the 160 kDa SR (sarcoplasmic reticulum) protein to be approx. 70% lower in mdx fibres when compared with normal skeletal muscles. This drastic reduction in SAR was confirmed by immunofluorescence microscopy. Patchy internal labelling of SAR in dystrophic fibres suggests an abnormal formation of SAR domains. Differential co-immunoprecipitation experiments and chemical cross-linking demonstrated a tight linkage between SAR and the SERCA1 (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase 1) isoform of the SR Ca2+-ATPase. However, the relative expression of the fast Ca2+ pump was not decreased in dystrophic membrane preparations. This implies that the reduction in SAR and calsequestrin-like proteins plays a central role in the previously reported impairment of Ca2+ buffering in the dystrophic SR [Culligan, Banville, Dowling and Ohlendieck (2002) J. Appl. Physiol. 92, 435–445]. Impaired Ca2+ shuttling between the Ca2+-uptake SERCA units and calsequestrin clusters via SAR, as well as an overall decreased luminal ion-binding capacity, might indirectly amplify the Ca2+-leak-channel-induced increase in cytosolic Ca2+ levels. This confirms the idea that abnormal Ca2+ cycling is involved in Ca2+-induced myonecrosis. Hence, manipulating disturbed Ca2+ handling might represent new modes of abolishing proteolytic degradation in muscular dystrophy.

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Dangain, J., and IR Neering. "Mouse Models of Muscular Dystrophy: Gene Products and Function." Physiology 7, no. 5 (October 1, 1992): 195–99. http://dx.doi.org/10.1152/physiologyonline.1992.7.5.195.

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With the discovery of the X-linked gene product dystrophin, the mdx mouse came to be regarded as the only suitable mouse model of human muscular dystrophy. However, existence of an autosomal gene homologous with dystrophin, together with physiological evidence of membrane fragility, reestablishes autosomal mouse mutants (dy, dy2j) as valid models.

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Bujold, Mathieu, Nicolas Caron, Goeffrey Camiran, Santwana Mukherjee, Paul D. Allen, Jacques P. Tremblay, and Yaming Wang. "Autotransplantation in mdx Mice of mdx Myoblasts Genetically Corrected by an HSV-1 Amplicon Vector." Cell Transplantation 11, no. 8 (November 2002): 759–67. http://dx.doi.org/10.3727/000000002783985297.

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Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by a lack of dystrophin. To eliminate the need for immunosuppressive drugs, transplantation of genetically modified autologous myoblasts has been proposed as a possible therapy for this myopathy. An HSV-1 amplicon vector (HSVDGN), containing a 17.3-kb full-length MCK-driven mouse dystrophin cDNA, an eGFP gene, and a neomycin resistance gene driven by CMV or SV40 promoters, respectively, was constructed and used to transduce mdx primary myoblasts. The presence of the eGFP and neomycin resistance genes facilitated the evaluation of the initial transduction efficiency and the permanent transduction frequency. At low multiplicities of infection (MOI 1–5), the majority of myoblasts (60–90%) expressed GFP. The GFP-positive mdx myoblasts were sorted by FACS and selected with neomycin (300 μg/ml) for 2 weeks. Up to 2% of initially infected mdx myoblasts stably expressed the three transgenes without further selection at that time. These altered cells were grafted into the tibialis anterior muscles of 18 mdx mice. Some of the mice were immunosuppressed with FK506 due to the anticipation that eGFP and the product of neomycin resistance gene might be immunogenic. One month after transplantation, numerous muscle fibers expressing mouse dystrophin were detected by immunohistochemistry, in both immunosuppressed (10–50%) and nonimmunosuppressed (5–25%) mdx mice. Our results demonstrated the capability of permanently expressing a full-length dystrophin in dystrophic myoblasts with HSV-1 amplicon vector and raised the possibility of an eventual treatment of DMD based on the transplantation of genetically modified autologous myoblasts.

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McARDLE, Anne, Timothy R. HELLIWELL, Geoffrey J. BECKETT, Mariana CATAPANO, Anthony DAVIS, and Malcolm J. JACKSON. "Effect of propylthiouracil-induced hypothyroidism on the onset of skeletal muscle necrosis in dystrophin-deficient mdx mice." Clinical Science 95, no. 1 (July 1, 1998): 83–89. http://dx.doi.org/10.1042/cs0950083.

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1.Duchenne and Becker muscular dystrophies are X-linked disorders caused by defects in muscle dystrophin. The mdx mouse is an animal model for Duchenne muscular dystrophy which has a point mutation in the dystrophin gene, resulting in little (< 3%) or no expression of dystrophin in muscle. Mdx mice show a characteristic pattern of muscle necrosis and regeneration. Muscles are normal until the third postnatal week when widespread necrosis commences. This is followed by muscle regeneration, with the persistence of centrally nucleated fibres. 2.This work has examined the hypothesis that the onset of this muscle necrosis is associated with postnatal maturation of the thyroid endocrine system and that pharmacological inhibition of thyroid hormone synthesis delays the onset of muscle necrosis. 3.Serum T4 and T3 concentrations of mice were found to rise immediately before the onset of muscle necrosis in the mdx mouse, and induction of hypothyroidism by treatment of animals with propylthiouracil was found to delay the onset of muscle necrosis. 4.The results provide the first demonstration of experimental delay of muscle necrosis by manipulation of the endocrine system in muscle lacking dystrophin, and provide a novel insight into the way in which a lack of dystrophin interacts with postnatal development to precipitate muscle necrosis in the mdx mouse.

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Kwak, Dongmin, Guoxian Wei, LaDora V. Thompson, and Jong-Hee Kim. "Short-Term ONX-0914 Administration: Performance and Muscle Phenotype in Mdx Mice." International Journal of Environmental Research and Public Health 17, no. 14 (July 19, 2020): 5211. http://dx.doi.org/10.3390/ijerph17145211.

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Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease. Although the lack of dystrophin protein is the primary defect responsible for the development of DMD, secondary disease complications such as persistent inflammation contribute greatly to the pathogenesis and the time-dependent progression of muscle destruction. The immunoproteasome is a potential therapeutic target for conditions or diseases mechanistically linked to inflammation. In this study, we explored the possible effects of ONX-0914 administration, an inhibitor specific for the immunoproteasome subunit LMP7 (ß5i), on motor performance, muscular pathology and protein degradation in 7-week old MDX mice, an age when the dystrophic muscles show extensive degeneration and regeneration. ONX-0914 (10 mg/kg) was injected subcutaneously on Day 2, 4, and 6. The mice were evaluated for physical performance (walking speed and strength) on Day 1 and 8. We show that this short-term treatment of ONX-0914 in MDX mice did not alter strength nor walking speed. The physical performance findings were consistent with no change in muscle inflammatory infiltration, percentage of central nuclei and proteasome content. Taken together, muscle structure and function in the young adult MDX mouse model are not altered with ONX-0914 treatment, indicating the administration of ONX-0914 during this critical time period does not exhibit any detrimental effects and may be an effective treatment of secondary complications of muscular dystrophy after further investigations.

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Chan, S., S. I. Head, and J. W. Morley. "Branched fibers in dystrophic mdx muscle are associated with a loss of force following lengthening contractions." American Journal of Physiology-Cell Physiology 293, no. 3 (September 2007): C985—C992. http://dx.doi.org/10.1152/ajpcell.00128.2007.

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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.

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Meyers, Tatyana A., Jackie A. Heitzman, and DeWayne Townsend. "DMD carrier model with mosaic dystrophin expression in the heart reveals complex vulnerability to myocardial injury." Human Molecular Genetics 29, no. 6 (January 24, 2020): 944–54. http://dx.doi.org/10.1093/hmg/ddaa015.

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Abstract Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease that causes progressive muscle wasting and cardiomyopathy. This X-linked disease results from mutations of the DMD allele on the X-chromosome resulting in the loss of expression of the protein dystrophin. Dystrophin loss causes cellular dysfunction that drives the loss of healthy skeletal muscle and cardiomyocytes. As gene therapy strategies strive toward dystrophin restoration through micro-dystrophin delivery or exon skipping, preclinical models have shown that incomplete restoration in the heart results in heterogeneous dystrophin expression throughout the myocardium. This outcome prompts the question of how much dystrophin restoration is sufficient to rescue the heart from DMD-related pathology. Female DMD carrier hearts can shed light on this question, due to their mosaic cardiac dystrophin expression resulting from random X-inactivation. In this work, a dystrophinopathy carrier mouse model was derived by breeding male or female dystrophin-null mdx mice with a wild type mate. We report that these carrier hearts are significantly susceptible to injury induced by one or multiple high doses of isoproterenol, despite expressing ~57% dystrophin. Importantly, only carrier mice with dystrophic mothers showed mortality after isoproterenol. These findings indicate that dystrophin restoration in approximately half of the heart still allows for marked vulnerability to injury. Additionally, the discovery of divergent stress-induced mortality based on parental origin in mice with equivalent dystrophin expression underscores the need for better understanding of the epigenetic, developmental, and even environmental factors that may modulate vulnerability in the dystrophic heart.

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Menke, A., and H. Jockusch. "Extent of shock-induced membrane leakage in human and mouse myotubes depends on dystrophin." Journal of Cell Science 108, no. 2 (February 1, 1995): 727–33. http://dx.doi.org/10.1242/jcs.108.2.727.

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A lack of the cytoskeletal protein dystrophin causes muscle fiber necrosis in Duchenne/Becker muscular dystrophies (DMD/BMD) and in murine X-linked muscular dystrophy (MDX). However, no overt disease symptoms are observed in dystrophin-less cultured myotubes, and the biological function of dystrophin in normal muscle cells is still unknown. In this work, we have extended our studies on a model system, using hypoosmotic shock to determine stress resistance of muscle cells. In frozen sections of control human and mouse myotubes, dystrophin was shown to be localized at the cell periphery as in mature muscle fibers. Dystrophin-less DMD and MDX myotubes were more susceptible to hypoosmotic shock than controls, as monitored by the uptake of external horseradish peroxidase and release of the soluble enzymes creatinine kinase or pyruvate kinase and of radiolabelled proteins. Control experiments indicated that this difference is not due to differences in metabolism or ion fluxes. Treatment with cytochalasin D drastically increased the shock sensitivity of myotubes and abolished the difference between dystrophin-less and control cells. These results lend further support to the suggested stabilizing role of dystrophin in the context of the membrane-cytoskeletal complex.

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Gibson, A. J., J. Karasinski, J. Relvas, J. Moss, T. G. Sherratt, P. N. Strong, and D. J. Watt. "Dermal fibroblasts convert to a myogenic lineage in mdx mouse muscle." Journal of Cell Science 108, no. 1 (January 1, 1995): 207–14. http://dx.doi.org/10.1242/jcs.108.1.207.

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Duchenne muscular dystrophy is a primary muscle disease that manifests itself in young boys as a result of a defect in a gene located on the X-chromosome. This gene codes for dystrophin, a normal muscle protein that is located beneath the sarcolemma of muscle fibres. Therapies to alleviate this disease have centred on implanting normal muscle precursor cells into dystrophic fibres to compensate for the lack of this gene and its product. To date, donor cells for implantation in such therapy have been of myogenic origin, derived from paternal biopsies. Success in human muscle, however, has been limited and may reflect immune rejection problems. To overcome this problem the patient's own myogenic cells, with the dystrophin gene inserted, could be used, but this could lead to other problems, since these cells are those that are functionally compromised by the disease. Here, we report the presence of high numbers of dystrophin-positive fibres after implanting dermal fibroblasts from normal mice into the muscle of the mdx mouse-the genetic homologue of Duchenne muscular dystrophy. Dystrophin-positive fibres were also abundant in mdx muscle following the implantation of cloned dermal fibroblasts from the normal mouse. Our results suggest the in vivo conversion of these non-myogenic cells to the myogenic pathway resulting in the formation of dystrophin-positive muscle fibres in the deficient host. The use of dermal fibroblasts may provide an alternative approach to the previously attempted myoblast transfer therapy, which in human trials has yielded disappointing results.

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Dudley, Roy W. R., Maya Khairallah, Shawn Mohammed, Larry Lands, Christine Des Rosiers, and Basil J. Petrof. "Dynamic responses of the glutathione system to acute oxidative stress in dystrophic mouse (mdx) muscles." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 3 (September 2006): R704—R710. http://dx.doi.org/10.1152/ajpregu.00031.2006.

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The precise mechanisms underlying skeletal muscle damage in Duchenne muscular dystrophy (DMD) remain ill-defined. Functional ischemia during muscle activation, with subsequent reperfusion during rest, has been documented. Therefore, one possibility is the presence of increased oxidative stress. We applied a model of acute hindlimb ischemia/reperfusion (I/R) in mdx mice (genetic homolog of DMD) to evaluate dynamic in vivo responses of dystrophic muscles to this form of oxidative stress. Before the application of I/R, mdx muscles showed: 1) decreased levels of total glutathione (GSH) with an increased oxidized (GSSG)-to-reduced (GSH) glutathione ratio; 2) greater activity of the GSH-metabolizing enzymes glutathione peroxidase (GPx) and glutathione reductase; and 3) lower activity levels of NADP-linked isocitrate dehydrogenase (ICDH) and aconitase, two metabolic enzymes that are sensitive to inactivation by oxidative stress and also implicated in GSH regeneration. Interestingly, nondystrophic muscles subjected to I/R exhibited similar changes in total glutathione, GSSG/GSH, GPx, ICDH, and aconitase. In contrast, all of the above remained stable in mdx muscles subjected to I/R. Taken together, these results suggest that mdx muscles are chronically subjected to increased oxidative stress, leading to adaptive changes that attempt to protect (although only in part) the dystrophic muscles from acute I/R-induced oxidative stress. In addition, mdx muscles show significant impairment of the redox-sensitive metabolic enzymes ICDH and aconitase, which may further contribute to contractile dysfunction in dystrophic muscles.

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Yanay, Nurit, Moran Elbaz, Jenya Konikov-Rozenman, Sharona Elgavish, Yuval Nevo, Yakov Fellig, Malcolm Rabie, Stella Mitrani-Rosenbaum, and Yoram Nevo. "Pax7, Pax3 and Mamstr genes are involved in skeletal muscle impaired regeneration of dy2J/dy2J mouse model of Lama2-CMD." Human Molecular Genetics 28, no. 20 (July 26, 2019): 3369–90. http://dx.doi.org/10.1093/hmg/ddz180.

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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.

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Rouger, Karl, Martine Le Cunff, Marja Steenman, Marie-Claude Potier, Nathalie Gibelin, Claude A. Dechesne, and Jean J. Leger. "Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice." American Journal of Physiology-Cell Physiology 283, no. 3 (September 1, 2002): C773—C784. http://dx.doi.org/10.1152/ajpcell.00112.2002.

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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.

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Tanabe, Y., K. Esaki, and T. Nomura. "Skeletal muscle pathology in X chromosome-linked muscular dystrophy (mdx) mouse." Acta Neuropathologica 69, no. 1-2 (1986): 91–95. http://dx.doi.org/10.1007/bf00687043.

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Kurihara, Teruyuki, Masahiko Kishi, Nobuyuki Saito, Michiji Komoto, Takanobu Hidaka, and Masao Kinoshita. "Electrical myotonia and cataract in X-linked muscular dystrophy (mdx) mouse." Journal of the Neurological Sciences 99, no. 1 (October 1990): 83–92. http://dx.doi.org/10.1016/0022-510x(90)90202-x.

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Laws, Nicola, and Andrew Hoey. "Progression of kyphosis in mdx mice." Journal of Applied Physiology 97, no. 5 (November 2004): 1970–77. http://dx.doi.org/10.1152/japplphysiol.01357.2003.

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Spinal deformity in the form of kyphosis or kyphoscoliosis occurs in most patients with Duchenne muscular dystrophy (DMD), a fatal X-linked disorder caused by an absence of the subsarcolemmal protein dystrophin. Mdx mice, which also lack dystrophin, show thoracolumbar kyphosis that progresses with age. We hypothesize that paraspinal and respiratory muscle weakness and fibrosis are associated with the progression of spinal deformity in this mouse model, and similar to DMD patients there is evidence of altered thoracic conformation and area. We measured kyphosis in mdx and age-matched control mice by monthly radiographs and the application of a novel radiographic index, the kyphotic index, similar to that used in boys with DMD. Kyphotic index became significantly less in mdx at 9 mo of age (3.58 ± 0.12 compared with 4.27 ± 0.04 in the control strain; P ≤ 0.01), indicating more severe kyphosis, and remained less from 10 to 17 mo of age. Thoracic area in 17-mo-old mdx was reduced by 14% compared with control mice ( P ≤ 0.05). Peak tetanic tension was significantly lower in mdx and fell 47% in old mdx latissimus dorsi muscles, 44% in intercostal strips, and 73% in diaphragm strips ( P ≤ 0.05). Fibrosis of these muscles and the longissimus dorsi, measured by hydroxyproline analysis and histological grading of picrosirius red-stained sections, was greater in mdx ( P < 0.05). We conclude that kyphotic index is a useful measure in mdx and other kyphotic mouse strains, and assessment of paralumbar and accessory respiratory muscles enhance understanding of spinal deformity in muscular dystrophy.

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Hui, Tiankun, Hongyang Jing, Tian Zhou, Peng Chen, Ziyang Liu, Xia Dong, Min Yan, et al. "Increasing LRP4 diminishes neuromuscular deficits in a mouse model of Duchenne muscular dystrophy." Human Molecular Genetics 30, no. 17 (May 13, 2021): 1579–90. http://dx.doi.org/10.1093/hmg/ddab135.

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Abstract Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive wasting of skeletal muscles. The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, critical for the control of muscle contraction. The NMJ decline is observed in DMD patients, but the mechanism is unclear. LRP4 serves as a receptor for agrin, a proteoglycan secreted by motor neurons to induce NMJ, and plays a critical role in NMJ formation and maintenance. Interestingly, we found that protein levels of LRP4 were reduced both in muscles of the DMD patients and DMD model mdx mice. We explored whether increasing LRP4 is beneficial for DMD and crossed muscle-specific LRP4 transgenic mice with mdx mice (mdx; HSA-LRP4). The LRP4 transgene increased muscle strength, together with improved neuromuscular transmission in mdx mice. Furthermore, we found the LRP4 expression mitigated NMJ fragments and denervation in mdx mice. Mechanically, we showed that overexpression of LRP4 increased the activity of MuSK and expression of dystrophin-associated glycoprotein complex proteins in the mdx mice. Overall, our findings suggest that increasing LRP4 improves both function and structure of NMJ in the mdx mice and Agrin signaling might serve as a new therapeutic strategy in DMD.

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Barton, Elisabeth R., Linda Morris, Antonio Musaro, Nadia Rosenthal, and H. Lee Sweeney. "Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice." Journal of Cell Biology 157, no. 1 (April 1, 2002): 137–48. http://dx.doi.org/10.1083/jcb.200108071.

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Duchenne muscular dystrophy is an X-linked degenerative disorder of muscle caused by the absence of the protein dystrophin. A major consequence of muscular dystrophy is that the normal regenerative capacity of skeletal muscle cannot compensate for increased susceptibility to damage, leading to repetitive cycles of degeneration–regeneration and ultimately resulting in the replacement of muscle fibers with fibrotic tissue. Because insulin-like growth factor I (IGF-I) has been shown to enhance muscle regeneration and protein synthetic pathways, we asked whether high levels of muscle-specific expression of IGF-I in mdx muscle could preserve muscle function in the diseased state. In transgenic mdx mice expressing mIgf-I (mdx:mIgf+/+), we showed that muscle mass increased by at least 40% leading to similar increases in force generation in extensor digitorum longus muscles compared with those from mdx mice. Diaphragms of transgenic mdx:mIgf+/+ exhibited significant hypertrophy and hyperplasia at all ages observed. Furthermore, the IGF-I expression significantly reduced the amount of fibrosis normally observed in diaphragms from aged mdx mice. Decreased myonecrosis was also observed in diaphragms and quadriceps from mdx:mIgf+/+ mice when compared with age-matched mdx animals. Finally, signaling pathways associated with muscle regeneration and protection against apoptosis were significantly elevated. These results suggest that a combination of promoting muscle regenerative capacity and preventing muscle necrosis could be an effective treatment for the secondary symptoms caused by the primary loss of dystrophin.

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Chao, D. S., J. R. Gorospe, J. E. Brenman, J. A. Rafael, M. F. Peters, S. C. Froehner, E. P. Hoffman, J. S. Chamberlain, and D. S. Bredt. "Selective loss of sarcolemmal nitric oxide synthase in Becker muscular dystrophy." Journal of Experimental Medicine 184, no. 2 (August 1, 1996): 609–18. http://dx.doi.org/10.1084/jem.184.2.609.

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Becker muscular dystrophy is an X-linked disease due to mutations of the dystrophin gene. We now show that neuronal-type nitric oxide synthase (nNOS), an identified enzyme in the dystrophin complex, is uniquely absent from skeletal muscle plasma membrane in many human Becker patients and in mouse models of dystrophinopathy. An NH2-terminal domain of nNOS directly interacts with alpha 1-syntrophin but not with other proteins in the dystrophin complex analyzed. However, nNOS does not associate with alpha 1-syntrophin on the sarcolemma in transgenic mdx mice expressing truncated dystrophin proteins. This suggests a ternary interaction of nNOS, alpha 1-syntrophin, and the central domain of dystrophin in vivo, a conclusion supported by developmental studies in muscle. These data indicate that proper assembly of the dystrophin complex is dependent upon the structure of the central rodlike domain and have implications for the design of dystrophin-containing vectors for gene therapy.

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Geissinge, H. D., and L. D. Rhodes. "Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice." Proceedings, annual meeting, Electron Microscopy Society of America 45 (August 1987): 726–27. http://dx.doi.org/10.1017/s0424820100127943.

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A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

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Al-Mshhdani, Basma A., Miranda D. Grounds, Peter G. Arthur, and Jessica R. Terrill. "A Blood Biomarker for Duchenne Muscular Dystrophy Shows That Oxidation State of Albumin Correlates with Protein Oxidation and Damage in Mdx Muscle." Antioxidants 10, no. 8 (August 3, 2021): 1241. http://dx.doi.org/10.3390/antiox10081241.

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Duchenne muscular dystrophy (DMD) is a severe X-linked muscle wasting disease with no cure. While the precise mechanisms of progressive dystropathology remain unclear, oxidative stress caused by excessive generation of oxidants is strongly implicated. Blood biomarkers that could track oxidant levels in tissues would be valuable to measure the effectiveness of clinical treatments for DMD; our research has focused on developing such biomarkers. One target of oxidants that has the potential to be harnessed as a clinical biomarker is the thiol side chain of cysteine 34 (Cys34) of the blood protein albumin. This study using the mdx mouse model of DMD shows that in plasma, albumin Cys34 undergoes thiol oxidation and these changes correlate with levels of protein thiol oxidation and damage of the dystrophic muscles. A comparison with the commonly used biomarker protein carbonylation, confirmed that albumin thiol oxidation is the more sensitive plasma biomarker of oxidative stress occurring in muscle tissue. We show that plasma albumin oxidation reflects muscle dystropathology, as increased after exercise and decreased after taurine treatment of mdx mice. These data support the use of albumin thiol oxidation as a blood biomarker of dystropathology to assist with advancing clinical development of therapies for DMD.

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Rae, Mark G., and Dervla O'Malley. "Cognitive dysfunction in Duchenne muscular dystrophy: a possible role for neuromodulatory immune molecules." Journal of Neurophysiology 116, no. 3 (September 1, 2016): 1304–15. http://dx.doi.org/10.1152/jn.00248.2016.

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Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive physical disability, immobility, and premature death in affected boys. Underlying the devastating symptoms of DMD is the loss of dystrophin, a structural protein that connects the extracellular matrix to the cell cytoskeleton and provides protection against contraction-induced damage in muscle cells, leading to chronic peripheral inflammation. However, dystrophin is also expressed in neurons within specific brain regions, including the hippocampus, a structure associated with learning and memory formation. Linked to this, a subset of boys with DMD exhibit nonprogressing cognitive dysfunction, with deficits in verbal, short-term, and working memory. Furthermore, in the genetically comparable dystrophin-deficient mdx mouse model of DMD, some, but not all, types of learning and memory are deficient, and specific deficits in synaptogenesis and channel clustering at synapses has been noted. Little consideration has been devoted to the cognitive deficits associated with DMD compared with the research conducted into the peripheral effects of dystrophin deficiency. Therefore, this review focuses on what is known about the role of full-length dystrophin (Dp427) in hippocampal neurons. The importance of dystrophin in learning and memory is assessed, and the potential importance that inflammatory mediators, which are chronically elevated in dystrophinopathies, may have on hippocampal function is also evaluated.

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Nguyen, T. M., J. M. Ellis, D. R. Love, K. E. Davies, K. C. Gatter, G. Dickson, and G. E. Morris. "Localization of the DMDL gene-encoded dystrophin-related protein using a panel of nineteen monoclonal antibodies: presence at neuromuscular junctions, in the sarcolemma of dystrophic skeletal muscle, in vascular and other smooth muscles, and in proliferating brain cell lines." Journal of Cell Biology 115, no. 6 (December 15, 1991): 1695–700. http://dx.doi.org/10.1083/jcb.115.6.1695.

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mAbs have been raised against different epitopes on the protein product of the DMDL gene, which is an autosomal homologue of the X-linked DMD gene for dystrophin. These antibodies provide direct evidence that DMDL protein is localized near acetylcholine receptors at neuromuscular junctions in normal and mdx mouse intercostal muscle. The primary location in tissues other than skeletal muscle is smooth muscle, especially in the vascular system, which may account for the wide tissue distribution previously demonstrated by Western blotting. The DMDL protein was undetectable in the nonjunctional sarcolemma of normal human muscle, but was observed in nonjunctional sarcolemma of Duchenne muscular dystrophy patients, where dystrophin itself is absent or greatly reduced. The expression of DMDL protein is not restricted to smooth and skeletal muscle, however, since relatively large amounts are present in transformed brain cell lines of both glial and Schwann cell origin. This contrasts with the low levels of DMDL protein in adult brain tissue.

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Viola, Helena M., Stefan M. K. Davies, Aleksandra Filipovska, and Livia C. Hool. "L-type Ca2+ channel contributes to alterations in mitochondrial calcium handling in the mdx ventricular myocyte." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 6 (March 15, 2013): H767—H775. http://dx.doi.org/10.1152/ajpheart.00700.2012.

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The L-type Ca2+ channel is the main route for calcium entry into cardiac myocytes, and it is essential for contraction. Alterations in whole cell L-type Ca2+ channel current and Ca2+ homeostasis have been implicated in the development of cardiomyopathies. Cytoskeletal proteins can influence whole cell L-type Ca2+ current and mitochondrial function. Duchenne muscular dystrophy is a fatal X-linked disease that leads to progressive muscle weakness due to the absence of cytoskeletal protein dystrophin. This includes dilated cardiomyopathy, but the mechanisms are not well understood. We sought to identify the effect of alterations in whole cell L-type Ca2+ channel current on mitochondrial function in the murine model of Duchenne muscular dystrophy ( mdx). Activation of the L-type Ca2+ channel with the dihydropyridine agonist BayK(−) caused a significantly larger increase in cytosolic Ca2+ in mdx vs. wild-type ( wt) ventricular myocytes. Consistent with elevated cytosolic Ca2+, resting mitochondrial Ca2+, NADH, and mitochondrial superoxide were significantly greater in mdx vs. wt myocytes. Activation of the channel with BayK(−) caused a further increase in mitochondrial Ca2+, NADH, and superoxide in mdx myocytes. The ratios of the increases were similar to the ratios recorded in wt myocytes. In mitochondria isolated from 8-wk-old mdx hearts, respiration and mitochondrial electron transport chain complex activity were similar to mitochondria isolated from wt hearts. We conclude that mitochondria function at a higher level of resting calcium in the intact mdx myocyte and activation of the L-type Ca2+ channel contributes to alterations in calcium handling by the mitochondria. This perturbation may contribute to the development of cardiomyopathy.

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Siemionow, Maria, M. Malik, P. Langa, J. Cwykiel, S. Brodowska, and A. Heydemann. "Cardiac Protection after Systemic Transplant of Dystrophin Expressing Chimeric (DEC) Cells to the mdx Mouse Model of Duchenne Muscular Dystrophy." Stem Cell Reviews and Reports 15, no. 6 (October 15, 2019): 827–41. http://dx.doi.org/10.1007/s12015-019-09916-0.

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Abstract Duchenne Muscular Dystrophy (DMD) is a progressive lethal disease caused by X-linked mutations of the dystrophin gene. Dystrophin deficiency clinically manifests as skeletal and cardiac muscle weakness, leading to muscle wasting and premature death due to cardiac and respiratory failure. Currently, no cure exists. Since heart disease is becoming a leading cause of death in DMD patients, there is an urgent need to develop new more effective therapeutic strategies for protection and improvement of cardiac function. We previously reported functional improvements correlating with dystrophin restoration following transplantation of Dystrophin Expressing Chimeric Cells (DEC) of myoblast origin in the mdx and mdx/scid mouse models. Here, we confirm positive effect of DEC of myoblast (MBwt/MBmdx) and mesenchymal stem cells (MBwt/MSCmdx) origin on protection of cardiac function after systemic DEC transplant. Therapeutic effect of DEC transplant (0.5 × 106) was assessed by echocardiography at 30 and 90 days after systemic-intraosseous injection to the mdx mice. At 90 days post-transplant, dystrophin expression in cardiac muscles of DEC injected mice significantly increased (15.73% ± 5.70 –MBwt/MBmdx and 5.22% ± 1.10 – MBwt/MSCmdx DEC) when compared to vehicle injected controls (2.01% ± 1.36) and, correlated with improved ejection fraction and fractional shortening on echocardiography. DEC lines of MB and MSC origin introduce a new promising approach based on the combined effects of normal myoblasts with dystrophin delivery capacities and MSC with immunomodulatory properties. Our study confirms feasibility and efficacy of DEC therapy on cardiac function and represents a novel therapeutic strategy for cardiac protection and muscle regeneration in DMD.

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Dell'Agnola, Chiara, Zejing Wang, Rainer Storb, Stephen J. Tapscott, Christian S. Kuhr, Stephen D. Hauschka, Richard S. Lee, et al. "Hematopoietic stem cell transplantation does not restore dystrophin expression in Duchenne muscular dystrophy dogs." Blood 104, no. 13 (December 15, 2004): 4311–18. http://dx.doi.org/10.1182/blood-2004-06-2247.

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Abstract Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene on the X-chromosome that result in skeletal and cardiac muscle damage and premature death. Studies in mice, including the mdx mouse model of DMD, have demonstrated that circulating bone marrow–derived cells can participate in skeletal muscle regeneration, but the potential clinical utility of treating human DMD by allogeneic marrow transplantation from a healthy donor remains unknown. To assess whether allogeneic hematopoietic cell transplantation (HCT) provides clinically relevant levels of donor muscle cell contribution in dogs with canine X-linked muscular dystrophy (c-xmd), 7 xmd dogs were given hematopoietic cell (HC) transplants from nonaffected littermates. Compared with the pretransplantation baseline, the number of dystrophin-positive fibers and the amount of wild-type dystrophin RNA did not increase after HCT, with observation periods ranging from 28 to 417 days. Similar results were obtained when the recipient dogs were given granulocyte colony-stimulating factor (G-CSF) after their initial transplantation to mobilize the cells. Despite successful allogeneic HCT and a permissive environment for donor muscle engraftment, there was no detectable contribution of bone marrow–derived cells to either skeletal muscle or muscle precursor cells assayed by clonal analyses at a level of sensitivity that should detect as little as 0.1% donor contribution.

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Pasternak, C., S. Wong, and E. L. Elson. "Mechanical function of dystrophin in muscle cells." Journal of Cell Biology 128, no. 3 (February 1, 1995): 355–61. http://dx.doi.org/10.1083/jcb.128.3.355.

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We have directly measured the contribution of dystrophin to the cortical stiffness of living muscle cells and have demonstrated that lack of dystrophin causes a substantial reduction in stiffness. The inferred molecular structure of dystrophin, its preferential localization underlying the cell surface, and the apparent fragility of muscle cells which lack this protein suggest that dystrophin stabilizes the sarcolemma and protects the myofiber from disruption during contraction. Lacking dystrophin, the muscle cells of persons with Duchenne muscular dystrophy (DMD) are abnormally vulnerable. These facts suggest that muscle cells with dystrophin should be stiffer than similar cells which lack this protein. We have tested this hypothesis by measuring the local stiffness of the membrane skeleton of myotubes cultured from mdx mice and normal controls. Like humans with DMD mdx mice lack dystrophin due to an x-linked mutation and provide a good model for the human disease. Deformability was measured as the resistance to indentation of a small area of the cell surface (to a depth of 1 micron) by a glass probe 1 micron in radius. The stiffness of the membrane skeleton was evaluated as the increment of force (mdyne) per micron of indentation. Normal myotubes with an average stiffness value of 1.23 +/- 0.04 (SE) mdyne/micron were about fourfold stiffer than myotubes cultured from mdx mice (0.34 +/- 0.014 mdyne/micron). We verified by immunofluorescence that both normal and mdx myotubes, which were at a similar developmental stage, expressed sarcomeric myosin, and that dystrophin was detected, diffusely distributed, only in normal, not in mdx myotubes. These results confirm that dystrophin and its associated proteins can reinforce the myotube membrane skeleton by increasing its stiffness and that dystrophin function and, therefore, the efficiency of therapeutic restoration of dystrophin can be assayed through its mechanical effects on muscle cells.

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Kress, W., T. Grimm, C. R. Müller, H. Keller, and R. Bittner. "Parental Source Effect on Inherited Mutations in the Dystrophin Gene of Mice and Humans." Acta geneticae medicae et gemellologiae: twin research 45, no. 1-2 (April 1996): 251–53. http://dx.doi.org/10.1017/s0001566000001409.

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Skewed X inactivation has been suspected as the genetic cause for some female carriers of Duchenne/Becker muscular dystrophy (DMD/BMD) presenting symptoms [1], as well as in manifesting females in other X-linked recessive diseases. No clear “parental source effect” – a difference in phenotype depending upon transmission of the mutated allele by either the father or the mother – has been observed [Cremer]. To date, most studies in this field have analysed the methylation status of flanking polymorphic sites (a measure of the maintenance of X inactivation and imprinting), not the expression of the causal gene itself.To test the parental source effect on the protein expression of the dystrophin gene, we have set up crosses of mdx/mdx and mdx/y mice – the well-known DMD animal model [2] with the respective wild-type mice of the same strain (Table 1). The obligate heterozygous F1 females show a mosaic expression of dystrophin in skeletal and cardiac muscle upon immunehistological staining. Because the source of the mutation in the litters is well defined, the mosaic pattern should reflect a parental source effect, if any. Such an effect should also change the level of muscle enzymes in serum and may thus be easily testable in humans, too. Since DMD is genetically lethal in humans, one can test the hypothesis of a parental source effect in BMD families only.

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Shibuya, S., and Y. Wakayama. "Freeze-fracture studies of myofiber plasma membrane in X chromosome-linked muscular dystrophy (mdx) mice." Acta Neuropathologica 76, no. 2 (1988): 179–84. http://dx.doi.org/10.1007/bf00688102.

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Lessa, Thais Borges, Rafael Cardoso Carvalho, Júlio David Spagnolo, Luis Claudio Lopes Correia da Silva, Silvia Renata Gaido Cortopassi, and Carlos Eduardo Ambrósio. "Laparoscopic guided local injection in the X-linked muscular dystrophy mouse (mdx) diaphragm. An advance in experimental therapies for Duchenne Muscular Dystrophy." Acta Cirurgica Brasileira 29, no. 11 (November 2014): 715–20. http://dx.doi.org/10.1590/s0102-86502014001800004.

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Dowling, Paul, Margit Zweyer, Maren Raucamp, Michael Henry, Paula Meleady, Dieter Swandulla, and Kay Ohlendieck. "Dataset on the mass spectrometry-based proteomic profiling of the kidney from wild type and the dystrophic mdx-4cv mouse model of X-linked muscular dystrophy." Data in Brief 28 (February 2020): 105067. http://dx.doi.org/10.1016/j.dib.2019.105067.

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Klymiuk, N., C. Thirion, K. Burkhardt, A. Wuensch, S. Krause, A. Richter, B. Kessler, et al. "238 TAILORED PIG MODEL OF DUCHENNE MUSCULAR DYSTROPHY." Reproduction, Fertility and Development 24, no. 1 (2012): 231. http://dx.doi.org/10.1071/rdv24n1ab238.

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Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases in humans, affecting 1 in 3500 boys. It is characterised by progressive muscle weakness and wasting due to mutations in the dystrophin (DMD) gene resulting in absence of dystrophin protein in skeletal muscle. Although curative treatments are currently not available, genetic and pharmacological approaches are under investigation including early-phase clinical trials. Existing animal models in different species (e.g. mdx mouse, GRMD dog) have been instrumental to understand the pathophysiology of DMD, but have several limitations. Importantly, the causative point mutations (mdx mouse: nonsense mutation; GRMD dog: splice mutation) are different from the most common human mutations (out-of-frame deletion of one or several exons of the DMD gene). We used gene targeting in somatic cells and nuclear transfer to generate a genetically tailored pig model of DMD. A bacterial artificial chromosome (BAC) from the porcine DMD gene was modified by recombineering to replace exon 52, resulting in a frame shift in the transcript. Modified BAC were transfected into male neonatal kidney cells, which were screened by quantitative polymerase chain reaction for replacement of exon 52 in the X-linked DMD gene. Eight of 436 cell clones were successfully targeted and 2 of them were used for nuclear transfer. For each of the cell clones, a pregnancy was established by transfer of cloned embryos into recipient gilts. Four piglets of the first litter were live born and killed within 48 h and tissue samples were processed for histological characterisation. Two piglets of the second litter died during birth due to obstetric complications, whereas the other 2 piglets were delivered by Caesarean section and raised in an artificial feeding system. Their serum creatine kinase (CK) levels were grossly elevated. Although both piglets showed reduced mobility compared with age-matched controls, they were able to move and feed on their own. Immunofluorescence staining of dystrophin was negative in muscle fibres of DMD mutant piglets and the complete absence of dystrophin protein was confirmed by immunoblot analysis. Histological examination of biceps femoris muscle from DMD mutant pigs showed a degenerative myopathy with fibre size variation, rounded fibres, central nuclei, fibrosis and fatty replacement of muscle tissue mimicking the hallmarks of the human disease. In conclusion, we generated the first pig model for a genetic muscle disease. The DMD mutant pig appears to be a bona fide model of the human dystrophy as ascertained by absence of the dystrophin protein, elevated serum CK levels and early degenerative changes on muscle histology. Because deletion of exon 52 is one of the most frequent mutations found in human DMD, the exon 52 mutated DMD pig represents an excellent model for testing targeted genetic treatments. This study was supported by the Bayerische Forschungsstiftung.

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Watt, Diana J., Janusz Karasinski, and Marjorie A. England. "Migration of lacZ positive cells from the tibialis anterior to the extensor digitorum longus muscle of the X-linked muscular dystrophic (mdx) mouse." Journal of Muscle Research and Cell Motility 14, no. 1 (February 1993): 121–32. http://dx.doi.org/10.1007/bf00132186.

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Sano, M., Y. Wada, K. Ii, E. Kominami, N. Katunuma, and H. Tsukagoshi. "Immunolocalization of cathepsins B, H and L in skeletal muscle of X-linked muscular dystrophy (mdx) mouse." Acta Neuropathologica 75, no. 3 (1988): 217–25. http://dx.doi.org/10.1007/bf00690529.

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Xin, Can, Xiangyu Chu, Wenzhong Wei, Biao Kuang, Yiqing Wang, Ying Tang, Jincao Chen, Hongbo You, Chengwen Li, and Bing Wang. "Combined gene therapy via VEGF and mini-dystrophin synergistically improves pathologies in temporalis muscle of dystrophin/utrophin double knockout mice." Human Molecular Genetics 30, no. 14 (May 13, 2021): 1349–59. http://dx.doi.org/10.1093/hmg/ddab120.

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Abstract Duchenne muscular dystrophy (DMD) is a severe X-linked inherited muscular disorder characterized by the loss of dystrophin. We have previously shown that monogene therapy using the mini-dystrophin gene improves muscle function in DMD. However, chronic inflammation plays an important role in progressive muscle degeneration in DMD as well. Vascular endothelial growth factor (VEGF) has been used to enhance muscle vasculature, reduce local inflammation and improve DMD muscle function. Temporalis muscles are the key skeletal muscles for mastication and loss of their function negatively affects DMD patient quality of life by reducing nutritional intake, but little is known about the pathology and treatment of the temporalis muscle in DMD. In this work, we tested the hypothesis that the combined delivery of the human mini-dystrophin and human VEGF genes to the temporalis muscles using separate recombinant adeno-associated viral (rAAV) vectors will synergistically improve muscle function and pathology in adult male dystrophin/utrophin double-knockout (mdx/utrn+/−) mice. The experimental mice were divided into four groups including: dystrophin + VEGF combined, dystrophin only, VEGF only and PBS control. After 2 months, gene expression and histological analysis of the temporalis muscles showed a synergistic improvement in temporalis muscle pathology and function coincident with increased restoration of dystrophin-associated protein complexes and nNOS in the dystrophin + VEGF combined group. We also observed significantly reduced inflammatory cell infiltration, central nucleation, and fibrosis in the dystrophin + VEGF combined group. We have demonstrated the efficacy of combined rAAV-mediated dystrophin and VEGF treatment of temporalis muscles in a DMD mouse model.

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Fukada, So-ichiro, Yuko Miyagoe-Suzuki, Hiroshi Tsukihara, Katsutoshi Yuasa, Saito Higuchi, Shiro Ono, Kazutake Tsujikawa, Shin'ichi Takeda, and Hiroshi Yamamoto. "Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice." Journal of Cell Science 115, no. 6 (March 15, 2002): 1285–93. http://dx.doi.org/10.1242/jcs.115.6.1285.

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The myogenic potential of bone marrow and fetal liver cells was examined using donor cells from green fluorescent protein (GFP)-gene transgenic mice transferred into chimeric mice. Lethally irradiated X-chromosome-linked muscular dystrophy (mdx) mice receiving bone marrow cells from the transgenic mice exhibited significant numbers of fluorescence+ and dystrophin+ muscle fibres. In order to compare the generating capacity of fetal liver cells with bone marrow cells in neonatal chimeras,these two cell types from the transgenic mice were injected into busulfantreated normal or mdx neonatal mice, and muscular generation in the chimeras was examined. Cardiotoxin-induced (or -uninduced, for mdx recipients) muscle regeneration in chimeras also produced fluorescence+ muscle fibres. The muscle reconstitution efficiency of the bone marrow cells was almost equal to that of fetal liver cells. However, the myogenic cell frequency was higher in fetal livers than in bone marrow. Among the neonatal chimeras of normal recipients, several fibres expressed the fluorescence in the cardiotoxin-untreated muscle. Moreover,fluorescence+ mononuclear cells were observed beneath the basal lamina of the cardiotoxin-untreated muscle of chimeras, a position where satellite cells are localizing. It was also found that mononuclear fluorescence+ and desmin+ cells were observed in the explantation cultures of untreated muscles of neonatal chimeras. The fluorescence+ muscle fibres were generated in the second recipient mice receiving muscle single cells from the cardiotoxin-untreated neonatal chimeras. The results suggest that both bone marrow and fetal liver cells may have the potential to differentiate into muscle satellite cells and participate in muscle regeneration after muscle damage as well as in physiological muscle generation.

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Lilling, Gilla, and Rivka Beitner. "Altered allosteric properties of cytoskeleton-bound phosphofructokinase in muscle from mice with X chromosome-linked muscular dystrophy (mdx)." Biochemical Medicine and Metabolic Biology 45, no. 3 (June 1991): 319–25. http://dx.doi.org/10.1016/0885-4505(91)90036-k.

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Frinchi, Monica, Giuseppe Morici, Giuseppa Mudó, Maria Bonsignore, and Valentina Di Liberto. "Beneficial Role of Exercise in the Modulation of mdx Muscle Plastic Remodeling and Oxidative Stress." Antioxidants 10, no. 4 (April 3, 2021): 558. http://dx.doi.org/10.3390/antiox10040558.

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Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive lethal disorder caused by the lack of dystrophin, which determines myofibers mechanical instability, oxidative stress, inflammation, and susceptibility to contraction-induced injuries. Unfortunately, at present, there is no efficient therapy for DMD. Beyond several promising gene- and stem cells-based strategies under investigation, physical activity may represent a valid noninvasive therapeutic approach to slow down the progression of the pathology. However, ethical issues, the limited number of studies in humans and the lack of consistency of the investigated training interventions generate loss of consensus regarding their efficacy, leaving exercise prescription still questionable. By an accurate analysis of data about the effects of different protocol of exercise on muscles of mdx mice, the most widely-used pre-clinical model for DMD research, we found that low intensity exercise, especially in the form of low speed treadmill running, likely represents the most suitable exercise modality associated to beneficial effects on mdx muscle. This protocol of training reduces muscle oxidative stress, inflammation, and fibrosis process, and enhances muscle functionality, muscle regeneration, and hypertrophy. These conclusions can guide the design of appropriate studies on human, thereby providing new insights to translational therapeutic application of exercise to DMD patients.

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Barraza-Flores, Pamela, Tatiana M. Fontelonga, Ryan D. Wuebbles, Hailey J. Hermann, Andreia M. Nunes, Joe N. Kornegay, and Dean J. Burkin. "Laminin-111 protein therapy enhances muscle regeneration and repair in the GRMD dog model of Duchenne muscular dystrophy." Human Molecular Genetics 28, no. 16 (April 24, 2019): 2686–95. http://dx.doi.org/10.1093/hmg/ddz086.

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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.

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Iyer, Shama R., Sameer B. Shah, Ana P. Valencia, Martin F. Schneider, Erick O. Hernández-Ochoa, Joseph P. Stains, Silvia S. Blemker, and Richard M. Lovering. "Altered nuclear dynamics in MDX myofibers." Journal of Applied Physiology 122, no. 3 (March 1, 2017): 470–81. http://dx.doi.org/10.1152/japplphysiol.00857.2016.

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Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to progressive muscle degeneration and weakness. Although the genetic basis is known, the pathophysiology of dystrophic skeletal muscle remains unclear. We examined nuclear movement in wild-type (WT) and muscular dystrophy mouse model for DMD (MDX) (dystrophin-null) mouse myofibers. We also examined expression of proteins in the linkers of nucleoskeleton and cytoskeleton (LINC) complex, as well as nuclear transcriptional activity via histone H3 acetylation and polyadenylate-binding nuclear protein-1. Because movement of nuclei is not only LINC dependent but also microtubule dependent, we analyzed microtubule density and organization in WT and MDX myofibers, including the application of a unique 3D tool to assess microtubule core structure. Nuclei in MDX myofibers were more mobile than in WT myofibers for both distance traveled and velocity. MDX muscle shows reduced expression and labeling intensity of nesprin-1, a LINC protein that attaches the nucleus to the microtubule and actin cytoskeleton. MDX nuclei also showed altered transcriptional activity. Previous studies established that microtubule structure at the cortex is disrupted in MDX myofibers; our analyses extend these findings by showing that microtubule structure in the core is also disrupted. In addition, we studied malformed MDX myofibers to better understand the role of altered myofiber morphology vs. microtubule architecture in the underlying susceptibility to injury seen in dystrophic muscles. We incorporated morphological and microtubule architectural concepts into a simplified finite element mathematical model of myofiber mechanics, which suggests a greater contribution of myofiber morphology than microtubule structure to muscle biomechanical performance.NEW & NOTEWORTHY Microtubules provide the means for nuclear movement but show altered organization in the muscular dystrophy mouse model (MDX) (dystrophin-null) muscle. Here, MDX myofibers show increased nuclear movement, altered transcriptional activity, and altered linkers of nucleoskeleton and cytoskeleton complex expression compared with healthy myofibers. Microtubule architecture was incorporated in finite element modeling of passive stretch, revealing a role of fiber malformation, commonly found in MDX muscle. The results suggest that alterations in microtubule architecture in MDX muscle affect nuclear movement, which is essential for muscle function.

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Hirn, Carole, George Shapovalov, Olivier Petermann, Emmanuelle Roulet, and Urs T. Ruegg. "Nav1.4 Deregulation in Dystrophic Skeletal Muscle Leads to Na+ Overload and Enhanced Cell Death." Journal of General Physiology 132, no. 2 (July 14, 2008): 199–208. http://dx.doi.org/10.1085/jgp.200810024.

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Duchenne muscular dystrophy (DMD) is a hereditary degenerative disease manifested by the absence of dystrophin, a structural, cytoskeletal protein, leading to muscle degeneration and early death through respiratory and cardiac muscle failure. Whereas the rise of cytosolic Ca2+ concentrations in muscles of mdx mouse, an animal model of DMD, has been extensively documented, little is known about the mechanisms causing alterations in Na+ concentrations. Here we show that the skeletal muscle isoform of the voltage-gated sodium channel, Nav1.4, which represents over 90% of voltage-gated sodium channels in muscle, plays an important role in development of abnormally high Na+ concentrations found in muscle from mdx mice. The absence of dystrophin modifies the expression level and gating properties of Nav1.4, leading to an increased Na+ concentration under the sarcolemma. Moreover, the distribution of Nav1.4 is altered in mdx muscle while maintaining the colocalization with one of the dystrophin-associated proteins, syntrophin α-1, thus suggesting that syntrophin is an important linker between dystrophin and Nav1.4. Additionally, we show that these modifications of Nav1.4 gating properties and increased Na+ concentrations are strongly correlated with increased cell death in mdx fibers and that both cell death and Na+ overload can be reversed by 3 nM tetrodotoxin, a specific Nav1.4 blocker.

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Journal articles on the topic 'Muscular dystrophic x-linked (mdx)'

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