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Mitochondria mdx

Marion Pauly, Claire Angebault-Prouteau, Haikel Dridi, Cécile Notarnicola, Valérie Scheuermann, Alain Lacampagne, Stefan Matecki, Jérémy Fauconnier
Besides its role in calcium (Ca(2+)) homeostasis, the sarco-endoplamic reticulum (SR/ER) controls protein folding and is tethered to mitochondria. Under pathophysiological conditions the unfolded protein response (UPR) is associated with disturbance in SR/ER-mitochondria crosstalk. Here, we investigated whether ER stress altered SR/ER-mitochondria links, Ca(2+) handling and muscle damage in WT (Wild Type) and mdx mice, the murine model of Duchenne Muscular Dystrophy (DMD). In WT mice, the SR/ER-mitochondria links were decreased in isolated FDB muscle fibers after injection of ER stress activator tunicamycin (TM)...
June 15, 2017: Biochimica et Biophysica Acta
Maria C Vila, Sree Rayavarapu, Marshall W Hogarth, Jack H Van der Meulen, Adam Horn, Aurelia Defour, Shin'ichi Takeda, Kristy J Brown, Yetrib Hathout, Kanneboyina Nagaraju, Jyoti K Jaiswal
Dystrophin deficiency is the genetic basis for Duchenne muscular dystrophy (DMD), but the cellular basis of progressive myofiber death in DMD is not fully understood. Using two dystrophin-deficient mdx mouse models, we find that the mitochondrial dysfunction is among the earliest cellular deficits of mdx muscles. Mitochondria in dystrophic myofibers also respond poorly to sarcolemmal injury. These mitochondrial deficits reduce the ability of dystrophic muscle cell membranes to repair and are associated with a compensatory increase in dysferlin-mediated membrane repair proteins...
February 2017: Cell Death and Differentiation
Victoria Kyrychenko, Eva Poláková, Radoslav Janíček, Natalia Shirokova
Duchenne muscular dystrophy (DMD) is a progressive muscle disease with severe cardiac complications. It is believed that cellular oxidative stress and augmented Ca(2+) signaling drives the development of cardiac pathology. Some mitochondrial and metabolic dysfunctions have also been reported. Here we investigate cellular mechanisms responsible for impaired mitochondrial metabolism in dystrophic cardiomyopathy at early stages of the disease. We employed electrophysiological and imaging techniques to study mitochondrial structure and function in cardiomyocytes from mdx mice, an animal model of DMD...
August 2015: Cell Calcium
Emma Rybalka, Cara A Timpani, Matthew B Cooke, Andrew D Williams, Alan Hayes
Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca2+ environment...
2014: PloS One
Christopher Ballmann, Katrin Hollinger, Joshua T Selsby, Rajesh Amin, John C Quindry
Patients with Duchenne muscular dystrophy (DMD) suffer from cardiac pathology causing up to 40% of all deaths resulting from fibrosis and cardiac complications. Quercetin is a flavonol with anti-inflammatory and antioxidant effects and is also a PGC-1α activator capable of antioxidant up-regulation, mitochondrial biogenesis, and prevention of cardiac complications. We sought to determine the extent to which dietary quercetin enrichment prevents (Experiment 1) and rescues (Experiment 2) cardiac pathology in mdx mice...
October 31, 2014: Experimental Physiology
Helena M Viola, Abbie M Adams, Stefan M K Davies, Susan Fletcher, Aleksandra Filipovska, Livia C Hool
Duchenne muscular dystrophy is a fatal X-linked disease characterized by the absence of dystrophin. Approximately 20% of boys will die of dilated cardiomyopathy that is associated with cytoskeletal protein disarray, contractile dysfunction, and reduced energy production. However, the mechanisms for altered energy metabolism are not yet fully clarified. Calcium influx through the L-type Ca(2+) channel is critical for maintaining cardiac excitation and contraction. The L-type Ca(2+) channel also regulates mitochondrial function and metabolic activity via transmission of movement of the auxiliary beta subunit through intermediate filament proteins...
July 15, 2014: Proceedings of the National Academy of Sciences of the United States of America
Sanjeewa A Goonasekera, Jennifer Davis, Jennifer Q Kwong, Federica Accornero, Lan Wei-LaPierre, Michelle A Sargent, Robert T Dirksen, Jeffery D Molkentin
Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca(2+) influx into myofibers leading to their death. Store-operated Ca(2+) entry (SOCE) through sarcolemmal Ca(2+) selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca(2+) entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca(2+) entry could induce muscular dystrophy...
July 15, 2014: Human Molecular Genetics
Gabriel A Alves, Luisa R Silva, Eloi F Rosa, Jeannine Aboulafia, Edna Freymüller-Haapalainen, Caden Souccar, Viviane L A Nouailhetas
Protein dystrophin is a component of the dystrophin-associated protein complex, which links the contractile machinery to the plasma membrane and to the extracellular matrix. Its absence leads to a condition known as Duchenne muscular dystrophy (DMD), a disease characterized by progressive skeletal muscle degeneration, motor disability, and early death. In mdx mice, the most common DMD animal model, loss of muscle cells is observed, but the overall disease alterations are less intense than in DMD patients. Alterations in gastrointestinal tissues from DMD patients and mdx mice are not yet completely understood...
February 2014: American Journal of Physiology. Gastrointestinal and Liver Physiology
Diem-Hang Nguyen-Tran, Nitai C Hait, Henrik Sperber, Junlin Qi, Karin Fischer, Nick Ieronimakis, Mario Pantoja, Aislinn Hays, Jeremy Allegood, Morayma Reyes, Sarah Spiegel, Hannele Ruohola-Baker
Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease. Studies in Drosophila showed that genetic increase of the levels of the bioactive sphingolipid sphingosine-1-phosphate (S1P) or delivery of 2-acetyl-5-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, suppresses dystrophic muscle degeneration. In the dystrophic mouse (mdx), upregulation of S1P by THI increases regeneration and muscle force. S1P can act as a ligand for S1P receptors and as a histone deacetylase (HDAC) inhibitor. Because Drosophila has no identified S1P receptors and DMD correlates with increased HDAC2 levels, we tested whether S1P action in muscle involves HDAC inhibition...
January 2014: Disease Models & Mechanisms
Helena M Viola, Stefan M K Davies, Aleksandra Filipovska, Livia C Hool
The L-type Ca(2+) channel is the main route for calcium entry into cardiac myocytes, and it is essential for contraction. Alterations in whole cell L-type Ca(2+) channel current and Ca(2+) homeostasis have been implicated in the development of cardiomyopathies. Cytoskeletal proteins can influence whole cell L-type Ca(2+) 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...
March 15, 2013: American Journal of Physiology. Heart and Circulatory Physiology
Justin M Percival, Michael P Siegel, Gary Knowels, David J Marcinek
Given the crucial roles for mitochondria in ATP energy supply, Ca(2+) handling and cell death, mitochondrial dysfunction has long been suspected to be an important pathogenic feature in Duchenne muscular dystrophy (DMD). Despite this foresight, mitochondrial function in dystrophin-deficient muscles has remained poorly defined and unknown in vivo. Here, we used the mdx mouse model of DMD and non-invasive spectroscopy to determine the impact of dystrophin-deficiency on skeletal muscle mitochondrial localization and oxidative phosphorylation function in vivo...
January 1, 2013: Human Molecular Genetics
Vanessa E Jahnke, Jack H Van Der Meulen, Helen K Johnston, Svetlana Ghimbovschi, Terrence Partridge, Eric P Hoffman, Kanneboyina Nagaraju
BACKGROUND: Duchenne muscular dystrophy is a genetic disease involving a severe muscle wasting that is characterized by cycles of muscle degeneration/regeneration and culminates in early death in affected boys. Mitochondria are presumed to be involved in the regulation of myoblast proliferation/differentiation; enhancing mitochondrial activity with exercise mimetics (AMPK and PPAR-delta agonists) increases muscle function and inhibits muscle wasting in healthy mice. We therefore asked whether metabolic remodeling agents that increase mitochondrial activity would improve muscle function in mdx mice...
2012: Skeletal Muscle
Richard Godin, Frederic Daussin, Stefan Matecki, Tong Li, Basil J Petrof, Yan Burelle
Alterations of mitochondrial function have been implicated in the pathogenesis of Duchenne muscular dystrophy. In the present study, mitochondrial respiratory function, reactive oxygen species (ROS) dynamics and susceptibility to Ca(2+)-induced permeability transition pore (PTP) opening were investigated in permeabilized skeletal muscle fibres of 6-week-old mdx mice, in order to characterize the magnitude and nature of mitochondrial dysfunction at an early post-necrotic stage of the disease. Short-term overexpression of the transcriptional co-activator PGC1α, achieved by in vivo plasmid transfection, was then performed to determine whether this intervention could prevent mitochondrial impairment and mitigate associated biochemical abnormalities...
November 1, 2012: Journal of Physiology
Marion Pauly, Frederic Daussin, Yan Burelle, Tong Li, Richard Godin, Jeremy Fauconnier, Christelle Koechlin-Ramonatxo, Gerald Hugon, Alain Lacampagne, Marjorie Coisy-Quivy, Feng Liang, Sabah Hussain, Stefan Matecki, Basil J Petrof
Duchenne muscular dystrophy (DMD) is characterized by myofiber death from apoptosis or necrosis, leading in many patients to fatal respiratory muscle weakness. Among other pathological features, DMD muscles show severely deranged metabolic gene regulation and mitochondrial dysfunction. Defective mitochondria not only cause energetic deficiency, but also play roles in promoting myofiber atrophy and injury via opening of the mitochondrial permeability transition pore. Autophagy is a bulk degradative mechanism that serves to augment energy production and eliminate defective mitochondria (mitophagy)...
August 2012: American Journal of Pathology
Kristen A Baltgalvis, Jarrod A Call, Gregory D Cochrane, Rhianna C Laker, Zhen Yan, Dawn A Lowe
PURPOSE: We tested the hypothesis that low-intensity exercise in mdx mice improves plantar flexor muscle contractile function, resistance to fatigue, and mitochondrial adaptations without exacerbating muscular dystrophy. METHODS: We subjected mdx mice to 12 wk of voluntary low-resistance wheel running (Run, n = 17) or normal cage activities (sedentary (Sed), n = 16) followed by in vivo analyses for plantar flexor torque generation and fatigue resistance or running capacity on a treadmill...
September 2012: Medicine and Science in Sports and Exercise
Rosemary A Schuh, Kathryn C Jackson, Ramzi J Khairallah, Christopher W Ward, Espen E Spangenburg
Measurement of mitochondrial function in skeletal muscle is a vital tool for understanding regulation of cellular bioenergetics. Currently, a number of different experimental approaches are employed to quantify mitochondrial function, with each involving either mechanically or chemically induced disruption of cellular membranes. Here, we describe a novel approach that allows for the quantification of substrate-induced mitochondria-driven oxygen consumption in intact single skeletal muscle fibers isolated from adult mice...
March 15, 2012: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Sanjeewa A Goonasekera, Chi K Lam, Douglas P Millay, Michelle A Sargent, Roger J Hajjar, Evangelia G Kranias, Jeffery D Molkentin
Muscular dystrophies (MDs) comprise a group of degenerative muscle disorders characterized by progressive muscle wasting and often premature death. The primary defect common to most MDs involves disruption of the dystrophin-glycoprotein complex (DGC). This leads to sarcolemmal instability and Ca(2+) influx, inducing cellular necrosis. Here we have shown that the dystrophic phenotype observed in δ-sarcoglycan–null (Sgcd(–/–)) mice and dystrophin mutant mdx mice is dramatically improved by skeletal muscle–specific overexpression of sarcoplasmic reticulum Ca(2+) ATPase 1 (SERCA1)...
March 2011: Journal of Clinical Investigation
Alexis Ascah, Maya Khairallah, Frédéric Daussin, Céline Bourcier-Lucas, Richard Godin, Bruce G Allen, Basil J Petrof, Christine Des Rosiers, Yan Burelle
Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic (mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice...
January 2011: American Journal of Physiology. Heart and Circulatory Physiology
Sara Menazza, Bert Blaauw, Tania Tiepolo, Luana Toniolo, Paola Braghetta, Barbara Spolaore, Carlo Reggiani, Fabio Di Lisa, Paolo Bonaldo, Marcella Canton
Several studies documented the key role of oxidative stress and abnormal production of reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies (MDs). The sources of ROS, however, are still controversial as well as their major molecular targets. This study investigated whether ROS produced in mitochondria by monoamine oxidase (MAO) contributes to MD pathogenesis. Pargyline, an MAO inhibitor, reduced ROS accumulation along with a beneficial effect on the dystrophic phenotype of Col6a1(-/-) mice, a model of Bethlem myopathy and Ullrich congenital MD, and mdx mice, a model of Duchenne MD...
November 1, 2010: Human Molecular Genetics
Yan Burelle, Maya Khairallah, Alexis Ascah, Bruce G Allen, Christian F Deschepper, Basil J Petrof, Christine Des Rosiers
While compelling evidence supports the central role of mitochondrial dysfunction in the pathogenesis of heart failure, there is comparatively less information available on mitochondrial alterations that occur prior to failure. Building on our recent work with the dystrophin-deficient mdx mouse heart, this review focuses on how early changes in mitochondrial functional phenotype occur prior to overt cardiomyopathy and may be a determinant for the development of adverse cardiac remodelling leading to failure...
February 2010: Journal of Molecular and Cellular Cardiology
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