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Jacek Dygut, Barbara Kalinowska, Mateusz Banach, Monika Piwowar, Leszek Konieczny, Irena Roterman
The presented analysis concerns the inter-domain and inter-protein interface in protein complexes. We propose extending the traditional understanding of the protein domain as a function of local compactness with an additional criterion which refers to the presence of a well-defined hydrophobic core. Interface areas in selected homodimers vary with respect to their contribution to share as well as individual (domain-specific) hydrophobic cores. The basic definition of a protein domain, i.e., a structural unit characterized by tighter packing than its immediate environment, is extended in order to acknowledge the role of a structured hydrophobic core, which includes the interface area...
October 18, 2016: International Journal of Molecular Sciences
Tahnee L Kennedy, Kristy Swiderski, Kate T Murphy, Stefan M Gehrig, Claire L Curl, Chanchal Chandramouli, Mark A Febbraio, Lea M D Delbridge, René Koopman, Gordon S Lynch
Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdx and dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdx and dko mice when the dystrophic pathology was already well established...
October 14, 2016: American Journal of Pathology
J Patrick Gonzalez, Sergii Kyrychenko, Victoria Kyrychenko, Joel S Schneider, Celine J Granier, Eric Himelman, Kevin Lahey, Qingshi Zhao, Ghassan Yehia, Yuan-Xiang Tao, Mantu Bhaumik, Natalia Shirokova, Diego Fraidenraich
Duchenne muscular dystrophy (DMD) is characterized by the loss of the protein dystrophin, leading to muscle fragility, progressive weakening, and susceptibility to mechanical stress. Although dystrophin-negative mdx mouse models have classically been used to study DMD, phenotypes appear mild compared to patients. As a result, characterization of muscle pathology, especially in the heart, has proven difficult. We report that injection of mdx embryonic stem cells (ESCs) into Wild Type (WT) blastocysts produces adult mouse chimeras with severe DMD phenotypes in the heart and skeletal muscle...
October 13, 2016: Stem Cells
Gang Li, Qing-Shan Li, Wen-Bin Li, Jian Wei, Wen-Kai Chang, Zhi Chen, Hu-Yun Qiao, Ying-Wei Jia, Jiang-Hua Tian, Bing-Sheng Liang
Denervation often results in skeletal muscle atrophy. Different mechanisms seem to be involved in the determination between denervated slow and fast skeletal muscle atrophy. At the epigenetic level, miRNAs are thought to be highly involved in the pathophysiological progress of denervated muscles. We used miRNA microarrays to determine miRNA expression profiles from a typical slow muscle (soleus muscle) and a typical fast muscle (tibialis anterior muscle) at an early denervation stage in a rat model. Results showed that miR-206, miR-195, miR-23a, and miR-30e might be key factors in the transformation process from slow to fast muscle in denervated slow muscles...
August 2016: Neural Regeneration Research
Joseph J Belanto, John T Olthoff, Tara L Mader, Christopher M Chamberlain, D'anna M Nelson, Preston M McCourt, Dana M Talsness, Gregg G Gunderson, Dawn A Lowe, James M Ervasti
Absence of the protein dystrophin causes Duchenne muscular dystrophy. Dystrophin directly binds to microtubules in vitro, and its absence in vivo correlates with disorganization of the subsarcolemmal microtubule lattice, increased detyrosination of α-tubulin, and altered redox signaling. We previously demonstrated that the dystrophin homologue utrophin neither binds microtubules in vitro nor rescues microtubule lattice organization when overexpressed in muscles of dystrophin-deficient mdx mice. Here, we fine-mapped the dystrophin domain necessary for microtubule binding to spectrin-like repeats 20-22...
September 16, 2016: Human Molecular Genetics
David W Hammers, Margaret M Sleeper, Sean C Forbes, Ai Shima, Glenn A Walter, H Lee Sweeney
BACKGROUND: Cardiomyopathy is a leading cause of mortality among Duchenne muscular dystrophy patients and lacks effective therapies. Phosphodiesterase type 5 is implicated in dystrophic pathology, and the phosphodiesterase type 5 inhibitor tadalafil has recently been studied in a clinical trial for Duchenne muscular dystrophy. METHODS AND RESULTS: Tadalafil was evaluated for the prevention of cardiomyopathy in the mdx mouse and golden retriever muscular dystrophy dog models of Duchenne muscular dystrophy...
2016: Journal of the American Heart Association
Mikako Ito, Yuka Ehara, Shin Li, Kosuke Inada, Kinji Ohno
Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by loss-of-function mutations in <i>DMD</i> encoding dystrophin. No rational therapy is currently available. Utrophin is a paralog of dystrophin and is highly expressed at the neuromuscular junction. In <i>mdx</i> mice, utrophin is naturally upregulated throughout the muscle fibers, which mitigates muscular dystrophy. We previously reported the protein-anchoring therapy, in which a recombinant extracellular matrix protein is delivered to and anchored to a specific target using its proprietary binding domains...
August 2, 2016: Human Gene Therapy
Brian J McMorran, Francis E McCarthy, Elizabeth M Gibbs, Mabel Pang, Jamie L Marshall, Alison V Nairn, Kelley W Moremen, Rachelle H Crosbie-Watson, Linda G Baum
The neuromuscular junction (NMJ) is enriched with glycoproteins modified with N-acetylgalactosamine (GalNAc) residues, and four nominally GalNAc-specific plant lectins have historically been used to identify the NMJ and the utrophin-glycoprotein complex (UGC). However, little is known about the specific glycan epitopes on skeletal muscle that are bound by these lectins, the glycoproteins that bear these epitopes, or how creation of these glycan epitopes is regulated. Here we profile changes in cell surface glycosylation during muscle cell differentiation, and identify distinct differences in the binding preferences of GalNAc specific lectins, Wisteria floribunda agglutinin (WFA), Vicia villosa agglutinin (VVA), soybean agglutinin (SBA), and Dolichos biflorus agglutinin (DBA)...
May 28, 2016: Glycobiology
Shang-Hang Shen, Ning Yu, Hao Xu, Xi-Yao Liu, Guo-Wei Tan, Zhan-Xiang Wang
BACKGROUND: Glioma is the most devastating brain tumor worldwide. Previous studies showed that UTRN (utrophin) was related to cancers, but its role in glioma cells remains uncovered. MATERIALS AND METHODS: RNAi was used to knockdown UTRN in U251 cells using lentivirus system. The knockdown efficiency was validated by real-time quantitative PCR. Cell proliferation, cell cycle, and apoptosis progression were determined by MTT, colony formation analysis, and flow cytometry analysis...
May 2016: Cancer Biotherapy & Radiopharmaceuticals
Marijana Sekulic-Jablanovic, Nina D Ullrich, David Goldblum, Anja Palmowski-Wolfe, Francesco Zorzato, Susan Treves
The orbicularis oculi are the sphincter muscles of the eyelids and are involved in modulating facial expression. They differ from both limb and extraocular muscles (EOMs) in their histology and biochemistry. Weakness of the orbicularis oculi muscles is a feature of neuromuscular disorders affecting the neuromuscular junction, and weakness of facial muscles and ptosis have also been described in patients with mutations in the ryanodine receptor gene. Here, we investigate human orbicularis oculi muscles and find that they are functionally more similar to quadriceps than to EOMs in terms of excitation-contraction coupling components...
May 2016: Journal of General Physiology
Valeria Ricotti, Stefan Spinty, Helen Roper, Imelda Hughes, Bina Tejura, Neil Robinson, Gary Layton, Kay Davies, Francesco Muntoni, Jonathon Tinsley
PURPOSE: SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. METHODS: This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A-C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10...
2016: PloS One
Elizabeth M van der Pijl, Maaike van Putten, Erik H Niks, Jan J G M Verschuuren, Annemieke Aartsma-Rus, Jaap J Plomp
Duchenne muscular dystrophy (DMD) is an X-linked myopathy caused by dystrophin deficiency. Dystrophin is present intracellularly at the sarcolemma, connecting actin to the dystrophin-associated glycoprotein complex. Interestingly, it is enriched postsynaptically at the neuromuscular junction (NMJ), but its synaptic function is largely unknown. Utrophin, a dystrophin homologue, is also concentrated at the NMJ, and upregulated in DMD. It is possible that the absence of dystrophin at NMJs in DMD causes neuromuscular transmission defects that aggravate muscle weakness...
June 2016: European Journal of Neuroscience
Narinder Janghra, Jennifer E Morgan, Caroline A Sewry, Francis X Wilson, Kay E Davies, Francesco Muntoni, Jonathon Tinsley
Duchenne muscular dystrophy is a severe and currently incurable progressive neuromuscular condition, caused by mutations in the DMD gene that result in the inability to produce dystrophin. Lack of dystrophin leads to loss of muscle fibres and a reduction in muscle mass and function. There is evidence from dystrophin-deficient mouse models that increasing levels of utrophin at the muscle fibre sarcolemma by genetic or pharmacological means significantly reduces the muscular dystrophy pathology. In order to determine the efficacy of utrophin modulators in clinical trials, it is necessary to accurately measure utrophin levels and other biomarkers on a fibre by fibre basis within a biopsy section...
2016: PloS One
Andoria Tjondrokoesoemo, Tobias G Schips, Michelle A Sargent, Davy Vanhoutte, Onur Kanisicak, Vikram Prasad, Suh-Chin J Lin, Marjorie Maillet, Jeffery D Molkentin
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin protein compromises the stability of the sarcolemma membrane surrounding each muscle cell fiber, leading to membrane ruptures and leakiness that induces myofiber necrosis, a subsequent inflammatory response, and progressive tissue fibrosis with loss of functional capacity. Cathepsin S (Ctss) is a cysteine protease that is actively secreted in areas of tissue injury and ongoing inflammation, where it participates in extracellular matrix remodeling and healing...
May 6, 2016: Journal of Biological Chemistry
Mariz Vainzof, Leticia Feitosa, Marta Canovas, Danielle Ayub-Guerrieri, Rita de Cássia M Pavanello, Mayana Zatz
Utrophin expression was investigated in two phenotypically discordant Duchenne muscular dystrophy half-brothers. The youngest was wheelchair-bound at age 9, while his mildly affected older brother was able to walk without difficulties at age 15. DNA analysis revealed an out-of-frame exon 2 duplication in the DMD gene, associated with muscle dystrophin protein deficiency. Utrophin localization and quantity was analyzed and compared in both sibs to verify whether this could explain the milder phenotype of the older brother...
March 2016: Neuromuscular Disorders: NMD
Andoria Tjondrokoesoemo, Tobias Schips, Onur Kanisicak, Michelle A Sargent, Jeffery D Molkentin
Muscular dystrophy (MD) is associated with mutations in genes that stabilize the myofiber plasma membrane, such as through the dystrophin-glycoprotein complex (DGC). Instability of this complex or defects in membrane repair/integrity leads to calcium influx and myofiber necrosis leading to progressive dystrophic disease. MD pathogenesis is also associated with increased skeletal muscle protease levels and activity that could augment weakening of the sarcolemma through greater degradation of cellular attachment complexes...
March 15, 2016: Human Molecular Genetics
Daria Wojtal, Dwi U Kemaladewi, Zeenat Malam, Sarah Abdullah, Tatianna W Y Wong, Elzbieta Hyatt, Zahra Baghestani, Sergio Pereira, James Stavropoulos, Vincent Mouly, Kamel Mamchaoui, Francesco Muntoni, Thomas Voit, Hernan D Gonorazky, James J Dowling, Michael D Wilson, Roberto Mendoza-Londono, Evgueni A Ivakine, Ronald D Cohn
Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD)...
January 7, 2016: American Journal of Human Genetics
Daniela L Rebolledo, Min Jeong Kim, Nicholas P Whitehead, Marvin E Adams, Stanley C Froehner
Nitric oxide (NO) is a key regulator of skeletal muscle function and metabolism, including vasoregulation, mitochondrial function, glucose uptake, fatigue and excitation-contraction coupling. The main generator of NO in skeletal muscle is the muscle-specific form of neuronal nitric oxide synthase (nNOSμ) produced by the NOS1 gene. Skeletal muscle nNOSμ is predominantly localized at the sarcolemma by interaction with the dystrophin protein complex (DPC). In Duchenne muscular dystrophy (DMD), loss of dystrophin leads to the mislocalization of nNOSμ from the sarcolemma to the cytosol...
January 1, 2016: Human Molecular Genetics
Sara Chiappalupi, Giovanni Luca, Francesca Mancuso, Luca Madaro, Francesca Fallarino, Carmine Nicoletti, Mario Calvitti, Iva Arato, Giulia Falabella, Laura Salvadori, Antonio Di Meo, Antonello Bufalari, Stefano Giovagnoli, Riccardo Calafiore, Rosario Donato, Guglielmo Sorci
Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle degeneration leading to impaired locomotion, respiratory failure and premature death. In DMD patients, inflammatory events secondary to dystrophin mutation play a major role in the progression of the pathology. Sertoli cells (SeC) have been largely used to protect xenogeneic engraftments or induce trophic effects thanks to their ability to secrete trophic, antiinflammatory, and immunomodulatory factors. Here we have purified SeC from specific pathogen-free (SPF)-certified neonatal pigs, and embedded them into clinical grade alginate microcapsules...
January 2016: Biomaterials
Christine Péladeau, Aatika Ahmed, Adel Amirouche, Tara E Crawford Parks, Lucas M Bronicki, Vladimir Ljubicic, Jean-Marc Renaud, Bernard J Jasmin
Upregulation of utrophin A is an attractive therapeutic strategy for treating Duchenne muscular dystrophy (DMD). Over the years, several studies revealed that utrophin A is regulated by multiple transcriptional and post-transcriptional mechanisms, and that pharmacological modulation of these pathways stimulates utrophin A expression in dystrophic muscle. In particular, we recently showed that activation of p38 signaling causes an increase in the levels of utrophin A mRNAs and protein by decreasing the functional availability of the destabilizing RNA-binding protein called K-homology splicing regulatory protein, thereby resulting in increases in the stability of existing mRNAs...
January 1, 2016: Human Molecular Genetics
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