Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy

• 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
• Format: Article
• Language: English
• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000806

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.