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Maria Siemionow, Joanna Cwykiel, Ahlke Heydemann, Jesus Garcia, Enza Marchese, Krzysztof Siemionow, Erzsebet Szilagyi
Duchenne Muscular Dystrophy (DMD) is a progressive and lethal disease caused by mutations of the dystrophin gene. Currently no cure exists. Stem cell therapies targeting DMD are challenged by limited engraftment and rejection despite the use of immunosuppression. There is an urgent need to introduce new stem cell-based therapies that exhibit low allogenic profiles and improved cell engraftment. In this proof-of-concept study, we develop and test a new human stem cell-based approach to increase engraftment, limit rejection, and restore dystrophin expression in the mdx/scid mouse model of DMD...
March 15, 2018: Stem Cell Reviews
Pavithra S Iyer, Lionel O Mavoungou, Flavio Ronzoni, Joanna Zemla, Emanuel Schmid-Siegert, Stefania Antonini, Laurence A Neff, Olivier M Dorchies, Marisa Jaconi, Malgorzata Lekka, Graziella Messina, Nicolas Mermod
Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease currently without cure. We investigated the use of the PiggyBac transposon for full-length dystrophin expression in murine mesoangioblast (MABs) progenitor cells. DMD murine MABs were transfected with transposable expression vectors for full-length dystrophin and transplanted intramuscularly or intra-arterially into mdx/SCID mice. Intra-arterial delivery indicated that the MABs could migrate to regenerating muscles to mediate dystrophin expression...
February 2, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Robert G Barker, Barnaby P Frankish, Hongyang Xu, Robyn M Murphy
Duchenne muscular dystrophy (DMD) patients and the dystrophic mdx mouse have an elevated demand for ATP requiring processes, including Ca2+ regulation and skeletal muscle regeneration. As a key substrate for cellular ATP production, altered glycogen metabolism may contribute significantly to dystrophic pathology and explain reports of mild glucose intolerance. We compare the soleus and extensor digitorum longus (EDL) muscles of the mdx mouse during active muscle necrosis (at 28 days) and at 70 days where pathology is stable...
March 2018: Physiological Reports
Nora Yucel, Alex C Chang, John W Day, Nadia Rosenthal, Helen M Blau
Duchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation...
2018: NPJ Regenerative Medicine
Mark A Aminzadeh, Russell G Rogers, Mario Fournier, Rachel E Tobin, Xuan Guan, Martin K Childers, Allen M Andres, David J Taylor, Ahmed Ibrahim, Xiangming Ding, Angelo Torrente, Joshua M Goldhaber, Michael Lewis, Roberta A Gottlieb, Ronald A Victor, Eduardo Marbán
Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy (DMD), affecting the heart as well as skeletal muscle. Here, we report that clinical-stage cardiac progenitor cells, known as cardiosphere-derived cells (CDCs), improve cardiac and skeletal myopathy in the mdx mouse model of DMD. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity, and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human induced pluripotent stem cell-derived Duchenne cardiomyocytes...
February 17, 2018: Stem Cell Reports
J Patrick Gonzalez, Jayalakshmi Ramachandran, Eric Himelman, Myriam A Badr, Chifei Kang, Julie Nouet, Nadezhda Fefelova, Lai-Hua Xie, Natalia Shirokova, Jorge E Contreras, Diego Fraidenraich
Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/-) mice were studied before (4-6 months) and after (10-15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/-) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/-) hearts...
February 2, 2018: Neuromuscular Disorders: NMD
Mikako Ito, Kinji Ohno
Endplate acetylcholinesterase (AChE) deficiency is a form of congenital myasthenic syndrome (CMS) caused by mutations in COLQ, which encodes collagen Q (ColQ). ColQ is an extracellular matrix (ECM) protein that anchors AChE to the synaptic basal lamina. Biglycan, encoded by BGN, is another ECM protein that binds to the dystrophin-associated protein complex (DAPC) on skeletal muscle, which links the actin cytoskeleton and ECM proteins to stabilize the sarcolemma during repeated muscle contractions. Upregulation of biglycan stabilizes the DPAC...
February 20, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
Marcel Veltrop, Laura van Vliet, Margriet Hulsker, Jill Claassens, Conny Brouwers, Cor Breukel, Jos van der Kaa, Margot M Linssen, Johan T den Dunnen, Sjef Verbeek, Annemieke Aartsma-Rus, Maaike van Putten
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease generally caused by reading frame disrupting mutations in the DMD gene resulting in loss of functional dystrophin protein. The reading frame can be restored by antisense oligonucleotide (AON)-mediated exon skipping, allowing production of internally deleted, but partially functional dystrophin proteins as found in the less severe Becker muscular dystrophy. Due to genetic variation between species, mouse models with mutations in the murine genes are of limited use to test and further optimize human specific AONs in vivo...
2018: PloS One
Eric L Bell, Robert W Shine, Peter Dwyer, Lyndsay Olson, Jennifer Truong, Ross Fredenburg, Matthew Goddeeris, Dominique Stickens, Effie Tozzo
Duchenne muscular dystrophy (DMD) is a recessive, fatal X-linked disease that is characterized by progressive skeletal muscle wasting due to the absence of dystrophin, which is an a essential protein that bridges the inner cytoskeleton and extra-cellular matrix. This study set out to characterize the mitochondria in primary muscle satellite cell derived myoblasts from mdx mice and wild type control mice. Compared to wild type derived cells the mdx derived cells have reduced mitochondrial bioenergetics and have fewer mitochondria...
February 16, 2018: Mitochondrion
Joseph X DiMario
Dystrophic skeletal muscle is characterized by fibrotic accumulation of extracellular matrix components that compromise muscle structure, function, and capacity for regeneration. Tissue fibrosis is often initiated and sustained through transforming growth factor β (TGFβ) signaling, and KLF10 is an immediate early gene that is transcriptionally activated in response to TGFβ signaling. It encodes a transcriptional regulator that mediates the effects of TGFβ signaling in a variety of cell types. This report presents results of investigation of the effects of loss of KLF10 gene expression in wild-type and dystrophic (mdx) skeletal muscle...
February 16, 2018: American Journal of Pathology
Xueqin Song, Ya Zhang, Zhigang Hou, Hongran Wu, Shan Lu, Jin Tang, Xuexiao Chen, Hongying Cui, Yuan Li, Yue Bi, Weisong Duan, Zhongyao Li, Chunyan Li
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by the absence of dystrophin. Vascular endothelial growth factor (VEGF) is a heparin-binding dimeric glycoprotein and principal angiogenic factor stimulating the migration, proliferation and expression of various genes in endothelial cells. Recently, VEGF was demonstrated to exhibit an antiapoptotic and direct myogenic effect, as well as to enhance muscle force restoration subsequent to traumatic injury. Therefore, the present study attempted to assess the muscle damage of VEGF overexpression in mdx mice...
February 2018: Experimental and Therapeutic Medicine
Nalinda B Wasala, Jin-Hong Shin, Yi Lai, Yongping Yue, Federica Montanaro, Dongsheng Duan
Heart disease is a major health threat for Duchenne/Becker muscular dystrophy patients and carriers. Expression of a 6 to 8-kb mini-dystrophin gene in the heart holds promise to dramatically change the disease course. However the mini-dystrophin gene cannot be easily studied with adeno-associated virus (AAV) gene delivery because the size of the minigene exceeds AAV packaging capacity. We previously studied cardiac protection of the ∆H2-R19 minigene using the cardiac specific transgenic approach. Although this minigene fully normalized skeletal muscle force, it only partially corrected ECG and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy...
February 13, 2018: Human Gene Therapy
Leonit Kiriaev, Sindy Kueh, John W Morley, Kathryn N North, Peter J Houweling, Stewart I Head
A striking pathological feature of dystrophinopathies is the presence of morphologically abnormal branched skeletal muscle fibers. The deterioration of muscle contractile function in Duchenne muscular dystrophy is accompanied by both an increase in number and complexity of these branched fibers. We propose that when number and complexity of branched fibers reaches a critical threshold, "tipping point" the branches in and of themselves are the site of contraction-induced rupture. In the present study, we use the dystrophic mdx mouse and littermate controls to study the pre-diseased dystrophic fast-twitch EDL muscle at 2-3-weeks, the peak myonecrotic phase at 6-9 weeks and finally "old" at 58-112 weeks...
February 7, 2018: American Journal of Physiology. Cell Physiology
Elias B Chahine, Jonathan C Cho, Marylee V Worley
OBJECTIVE: To review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosing, and administration of bezlotoxumab (BEZ), as well as its place in the prevention of Clostridium difficile infection (CDI) recurrence. DATA SOURCES: A search of PubMed and Google Scholar using the terms "bezlotoxumab," "CDB1," "MDX-1388," and "MK-6072" was performed. The manufacturer's website was also reviewed to further identify relevant information...
February 1, 2018: Consultant Pharmacist: the Journal of the American Society of Consultant Pharmacists
Sandra Murphy, Margit Zweyer, Michael Henry, Paula Meleady, Rustam R Mundegar, Dieter Swandulla, Kay Ohlendieck
The highly progressive neuromuscular disorder dystrophinopathy is triggered by primary abnormalities in the Dmd gene, which causes cytoskeletal instability and loss of sarcolemmal integrity. Comparative organellar proteomics was employed to identify sarcolemma-associated proteins with an altered concentration in dystrophic muscle tissue from the mdx-4cv mouse model of dystrophinopathy. A lectin agglutination method was used to prepare a sarcolemma-enriched fraction and resulted in the identification of 190 significantly changed protein species...
February 1, 2018: Journal of Proteomics
Cinzia Pisani, Georgios Strimpakos, Francesca Gabanella, Maria Grazia Di Certo, Annalisa Onori, Cinzia Severini, Siro Luvisetto, Stefano Farioli-Vecchioli, Irene Carrozzo, Antonio Esposito, Tamara Canu, Elisabetta Mattei, Nicoletta Corbi, Claudio Passananti
Up-regulation of the dystrophin-related gene utrophin represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy (DMD). In order to re-program the utrophin expression level in muscle, we engineered artificial zinc finger transcription factors (ZF-ATFs) that target the utrophin "A" promoter. We have previously shown that the ZF-ATF "Jazz", either by transgenic manipulation or by systemic adeno-associated viral delivery, induces significant rescue of muscle function in dystrophic "mdx" mice...
January 30, 2018: Biochimica et Biophysica Acta
James Anthony Loehr, Shang Wang, Tanya R Cully, Rituraj Pal, Irina V Larina, Kirill V Larin, George G Rodney
Skeletal muscle from mdx mice is characterized by increased Nox2 ROS, altered microtubule network, increased muscle stiffness, and decreased muscle/respiratory function. While microtubule de-tyrosination has been suggested to increase stiffness and Nox2 ROS production in isolated single myofibers, its role in altering tissue stiffness and muscle function has not been established. Because Nox2 ROS production is upregulated prior to microtubule network alterations and ROS affect microtubule formation, we investigated the role of Nox2 ROS in diaphragm tissue microtubule organization, stiffness and muscle/respiratory function...
January 30, 2018: ELife
Bongjun Kim, Jong-Ho Lee, Won Jong Jin, Hong-Hee Kim, Hyunil Ha, Zang Hee Lee
Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by uncontrolled joint inflammation and destruction of bone and cartilage. Previous studies have shown that C-X-C motif chemokine 10 (CXCL10) has important roles in RA development and that blocking CXCL10 expression effectively inhibits arthritis progression in animal models. However, clinical study using anti-CXCL10 monoclonal antibody (MDX-1100) to block CXCL10 expression in patients with RA did not show significant effectiveness...
January 26, 2018: European Journal of Pharmacology
Elizabeth M Gibbs, Rachelle H Crosbie-Watson
Measuring functional outcomes in the treatment of muscular dystrophy is an essential aspect of preclinical testing. The assessment of voluntary ambulation in mouse models is a non-invasive and reproducible activity assay that is directly analogous to measures of patient ambulation such as the 6-minute walk test and related mobility scores. Many common methods for testing mouse ambulation speed and distance are based on the open field test, where an animal's free movement within an arena is measured over time...
December 29, 2017: Journal of Visualized Experiments: JoVE
Robert G Barker, Victoria L Wyckelsma, Hongyang Xu, Robyn M Murphy
Mitochondrial dysfunction is a pathological feature of Duchenne muscular Dystrophy (DMD), a debilitating and fatal neuromuscular disorder characterised by progressive muscle wasting and weakness. Mitochondria are a source of cellular ATP and involved in Ca2+ regulation and apoptotic signalling. Ameliorating aberrant mitochondrial function has therapeutic potential for reducing DMD disease severity. The dystrophic mdx mouse exhibits peak muscle damage at 21-28d which stabilises after 8 weeks. The amino acid taurine is implicated in mitochondrial health and function, with endogenous concentrations low when measured during the cycle of peak muscle damage in mdx mice...
December 20, 2017: American Journal of Physiology. Cell Physiology
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