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This Article Full Text Full Text (PDF) Supplemental Videos All Versions of this Article: 294/4/H1550    most recent 01253.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Huebner, K. D. Articles by Anderson, J. E. Search for Related Content PubMed PubMed Citation Articles by Huebner, K. D. Articles by Anderson, J. E.

Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone

¹Department of Human Anatomy and Cell Science, Faculty of Medicine, and ²Department of Biological Sciences, Faculty of Science, and ³Division of Cardiology, Cardiac Sciences Department, Saint Boniface General Hospital and the Institute of Cardiovascular Sciences, Saint Boniface General Hospital Research Centre, University of Manitoba, Manitoba, Canada; ⁴Department of Animal Sciences, The Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot, Israel; and ⁵Institute of Animal Sciences, Volcani Center, Bet-Dagan, Israel

Submitted 29 October 2007 ; accepted in final form 5 February 2008

The effect of halofuginone (Halo) on established fibrosis in older mdx dystrophic muscle was investigated. Mice (8 to 9 mo) treated with Halo (or saline in controls) for 5, 10, or 12 wk were assessed weekly for grip strength and voluntary running. Echocardiography was performed at 0, 5, and 10 wk. Respiratory function and exercise-induced muscle damage were tested. Heart, quadriceps, diaphragm, and tibialis anterior muscles were collected to study fibrosis, collagen I and III expression, collagen content using a novel collagenase-digestion method, and cell proliferation. Hepatocyte growth factor and -smooth muscle actin proteins were assayed in quadriceps. Halo decreased fibrosis (diaphragm and quadriceps), collagen I and III expression, collagen protein, and smooth muscle actin content after 10 wk treatment. Muscle-cell proliferation increased at 5 wk, and hepatocyte growth factor increased by 10 wk treatment. Halo markedly improved both cardiac and respiratory function and reduced damage and improved recovery from exercise. The overall impact of established dystrophy and dysfunction in cardiac and skeletal muscles was reduced by Halo treatment. Marked improvements in vital-organ functions implicate Halo as a strong candidate drug to reduce morbidity and mortality in Duchenne muscular dystrophy.

collagen I/III; echocardiography; Ki67; hepatocyte growth factor; -smooth muscle actin