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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
Main Authors: Asai, Akihiro, Sahani, Nita, Kaneki, Masao, Ouchi, Yasuyoshi, Martyn, J A Jeevendra, Yasuhara, Shingo Egusa
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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.
doi_str_mv 10.1371/journal.pone.0000806
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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>
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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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