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Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy
Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i)...
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Published in: | PloS one 2007-08, Vol.2 (8), p.e806-e806 |
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description | Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i) whether functional ischemia is necessary to cause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage.
In vivo microscopy was used to document assays developed to measure intramuscular red blood cell flux, to quantify the amount of vasodilatory molecules produced from myofibers, and to determine the extent of myofiber damage. Reversal of functional ischemia via pharmacological manipulation prevented contraction-induced myofiber damage in mdx mice, the murine equivalent of DMD. This result indicates that functional ischemia is required for, and thus an essential cause of, muscle damage in mdx mice. Next, to determine whether functional ischemia alone is enough to explain the disease, the extent of ischemia and the amount of myofiber damage were compared both in control and mdx mice. In control mice, functional ischemia alone was found insufficient to cause a similar degree of myofiber damage observed in mdx mice. Additional mechanisms are likely contributing to cause more severe myofiber damage in mdx mice, suggestive of the existence of a "two-hit" mechanism in the pathogenesis of this disease.
Evidence was provided supporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, the first quantitative evidence for the "two-hit" mechanism in this disease was documented. Significantly, the vasoactive drug tadalafil, a phosphodiesterase 5 inhibitor, administered to mdx mice ameliorated muscle damage. |
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In vivo microscopy was used to document assays developed to measure intramuscular red blood cell flux, to quantify the amount of vasodilatory molecules produced from myofibers, and to determine the extent of myofiber damage. Reversal of functional ischemia via pharmacological manipulation prevented contraction-induced myofiber damage in mdx mice, the murine equivalent of DMD. This result indicates that functional ischemia is required for, and thus an essential cause of, muscle damage in mdx mice. Next, to determine whether functional ischemia alone is enough to explain the disease, the extent of ischemia and the amount of myofiber damage were compared both in control and mdx mice. In control mice, functional ischemia alone was found insufficient to cause a similar degree of myofiber damage observed in mdx mice. Additional mechanisms are likely contributing to cause more severe myofiber damage in mdx mice, suggestive of the existence of a "two-hit" mechanism in the pathogenesis of this disease.
Evidence was provided supporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, the first quantitative evidence for the "two-hit" mechanism in this disease was documented. Significantly, the vasoactive drug tadalafil, a phosphodiesterase 5 inhibitor, administered to mdx mice ameliorated muscle damage.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0000806</identifier><identifier>PMID: 17726536</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Anesthesiology ; Animals ; Apoptosis ; Blood ; Blood cells ; Blood flow ; Carbolines - therapeutic use ; Cardiovascular Disorders/Vascular Biology ; Cause-effect relationships ; Cell death ; Critical care ; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism ; Damage prevention ; Disease Models, Animal ; Duchenne's muscular dystrophy ; Dystrophy ; Endothelium ; Erythrocytes ; Gene expression ; Geomorphology ; Geriatrics ; Histology ; Hospitals ; Hydrogen Peroxide - metabolism ; In vivo methods and tests ; Inhibitors ; Ischemia ; Ischemia - complications ; Kinases ; Medical schools ; Medicine ; Metabolism ; Metabolites ; Mice ; Mice, Transgenic ; Microscopy ; Muscle Contraction ; Muscular dystrophy ; Muscular Dystrophy, Animal - drug therapy ; Muscular Dystrophy, Animal - enzymology ; Muscular Dystrophy, Animal - etiology ; Musculoskeletal system ; Neurological Disorders/Neuromuscular Diseases ; Neuroscience ; Neuroscience/Neurobiology of Disease and Regeneration ; Nitric oxide ; Nitric Oxide - biosynthesis ; Pathogenesis ; Pediatrics and Child Health/Developmental and Pediatric Neurology ; Pharmacology ; Phosphodiesterase ; Phosphodiesterase 5 Inhibitors ; Phosphodiesterase Inhibitors - therapeutic use ; Physiology/Cardiovascular Physiology and Circulation ; Prevention ; Rodents ; Studies ; Tadalafil ; Vasoactive agents ; Vasodilator agents</subject><ispartof>PloS one, 2007-08, Vol.2 (8), p.e806-e806</ispartof><rights>COPYRIGHT 2007 Public Library of Science</rights><rights>2007 Asai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Asai et al. 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c780t-9e7a48e6882c2063bb8d4e2568f4b7e464e1f3a8c29f3dd1bacee026851cb8d73</citedby><cites>FETCH-LOGICAL-c780t-9e7a48e6882c2063bb8d4e2568f4b7e464e1f3a8c29f3dd1bacee026851cb8d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1950207325/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1950207325?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17726536$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wong, Rachel</contributor><creatorcontrib>Asai, Akihiro</creatorcontrib><creatorcontrib>Sahani, Nita</creatorcontrib><creatorcontrib>Kaneki, Masao</creatorcontrib><creatorcontrib>Ouchi, Yasuyoshi</creatorcontrib><creatorcontrib>Martyn, J A Jeevendra</creatorcontrib><creatorcontrib>Yasuhara, Shingo Egusa</creatorcontrib><title>Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i) whether functional ischemia is necessary to cause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage.
In vivo microscopy was used to document assays developed to measure intramuscular red blood cell flux, to quantify the amount of vasodilatory molecules produced from myofibers, and to determine the extent of myofiber damage. Reversal of functional ischemia via pharmacological manipulation prevented contraction-induced myofiber damage in mdx mice, the murine equivalent of DMD. This result indicates that functional ischemia is required for, and thus an essential cause of, muscle damage in mdx mice. Next, to determine whether functional ischemia alone is enough to explain the disease, the extent of ischemia and the amount of myofiber damage were compared both in control and mdx mice. In control mice, functional ischemia alone was found insufficient to cause a similar degree of myofiber damage observed in mdx mice. Additional mechanisms are likely contributing to cause more severe myofiber damage in mdx mice, suggestive of the existence of a "two-hit" mechanism in the pathogenesis of this disease.
Evidence was provided supporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, the first quantitative evidence for the "two-hit" mechanism in this disease was documented. Significantly, the vasoactive drug tadalafil, a phosphodiesterase 5 inhibitor, administered to mdx mice ameliorated muscle damage.</description><subject>Analysis</subject><subject>Anesthesiology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Blood</subject><subject>Blood cells</subject><subject>Blood flow</subject><subject>Carbolines - therapeutic use</subject><subject>Cardiovascular Disorders/Vascular Biology</subject><subject>Cause-effect relationships</subject><subject>Cell death</subject><subject>Critical care</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism</subject><subject>Damage prevention</subject><subject>Disease Models, Animal</subject><subject>Duchenne's muscular dystrophy</subject><subject>Dystrophy</subject><subject>Endothelium</subject><subject>Erythrocytes</subject><subject>Gene expression</subject><subject>Geomorphology</subject><subject>Geriatrics</subject><subject>Histology</subject><subject>Hospitals</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>In vivo methods and tests</subject><subject>Inhibitors</subject><subject>Ischemia</subject><subject>Ischemia - complications</subject><subject>Kinases</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microscopy</subject><subject>Muscle Contraction</subject><subject>Muscular dystrophy</subject><subject>Muscular Dystrophy, Animal - drug therapy</subject><subject>Muscular Dystrophy, Animal - enzymology</subject><subject>Muscular Dystrophy, Animal - etiology</subject><subject>Musculoskeletal system</subject><subject>Neurological Disorders/Neuromuscular Diseases</subject><subject>Neuroscience</subject><subject>Neuroscience/Neurobiology of Disease and Regeneration</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - biosynthesis</subject><subject>Pathogenesis</subject><subject>Pediatrics and Child Health/Developmental and Pediatric Neurology</subject><subject>Pharmacology</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase 5 Inhibitors</subject><subject>Phosphodiesterase Inhibitors - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Asai, Akihiro</au><au>Sahani, Nita</au><au>Kaneki, Masao</au><au>Ouchi, Yasuyoshi</au><au>Martyn, J A Jeevendra</au><au>Yasuhara, Shingo Egusa</au><au>Wong, Rachel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2007-08-29</date><risdate>2007</risdate><volume>2</volume><issue>8</issue><spage>e806</spage><epage>e806</epage><pages>e806-e806</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i) whether functional ischemia is necessary to cause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage.
In vivo microscopy was used to document assays developed to measure intramuscular red blood cell flux, to quantify the amount of vasodilatory molecules produced from myofibers, and to determine the extent of myofiber damage. Reversal of functional ischemia via pharmacological manipulation prevented contraction-induced myofiber damage in mdx mice, the murine equivalent of DMD. This result indicates that functional ischemia is required for, and thus an essential cause of, muscle damage in mdx mice. Next, to determine whether functional ischemia alone is enough to explain the disease, the extent of ischemia and the amount of myofiber damage were compared both in control and mdx mice. In control mice, functional ischemia alone was found insufficient to cause a similar degree of myofiber damage observed in mdx mice. Additional mechanisms are likely contributing to cause more severe myofiber damage in mdx mice, suggestive of the existence of a "two-hit" mechanism in the pathogenesis of this disease.
Evidence was provided supporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, the first quantitative evidence for the "two-hit" mechanism in this disease was documented. Significantly, the vasoactive drug tadalafil, a phosphodiesterase 5 inhibitor, administered to mdx mice ameliorated muscle damage.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>17726536</pmid><doi>10.1371/journal.pone.0000806</doi><tpages>e806</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2007-08, Vol.2 (8), p.e806-e806 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1950207325 |
source | Publicly Available Content Database (Proquest) (PQ_SDU_P3); PubMed Central |
subjects | Analysis Anesthesiology Animals Apoptosis Blood Blood cells Blood flow Carbolines - therapeutic use Cardiovascular Disorders/Vascular Biology Cause-effect relationships Cell death Critical care Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism Damage prevention Disease Models, Animal Duchenne's muscular dystrophy Dystrophy Endothelium Erythrocytes Gene expression Geomorphology Geriatrics Histology Hospitals Hydrogen Peroxide - metabolism In vivo methods and tests Inhibitors Ischemia Ischemia - complications Kinases Medical schools Medicine Metabolism Metabolites Mice Mice, Transgenic Microscopy Muscle Contraction Muscular dystrophy Muscular Dystrophy, Animal - drug therapy Muscular Dystrophy, Animal - enzymology Muscular Dystrophy, Animal - etiology Musculoskeletal system Neurological Disorders/Neuromuscular Diseases Neuroscience Neuroscience/Neurobiology of Disease and Regeneration Nitric oxide Nitric Oxide - biosynthesis Pathogenesis Pediatrics and Child Health/Developmental and Pediatric Neurology Pharmacology Phosphodiesterase Phosphodiesterase 5 Inhibitors Phosphodiesterase Inhibitors - therapeutic use Physiology/Cardiovascular Physiology and Circulation Prevention Rodents Studies Tadalafil Vasoactive agents Vasodilator agents |
title | Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy |
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