Submitted on October 29, 2007
Accepted on February 5, 2008
Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone
Kyla D Huebner1, Davinder S Jassal2, Orna Halevy3, Mark Pines4, and Judy E Anderson1*
1 Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada
2 Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Canada
3 Department of Animal Sciences, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot, Israel
4 Institute of Animal Sciences, Volcani Center, Bet-Dagan, Israel
* To whom correspondence should be addressed. E-mail: janders{at}ms.umanitoba.ca.
The effect of halofuginone (Halo) on established fibrosis in older mdx dystrophic muscle was investigated. Mice (8-9-months) treated with Halo (or saline in controls) for 5, 10 or 12 weeks were assessed weekly for grip strength and voluntary running. Echocardiography was performed at 0, 5, and 10 weeks. 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 (HGF) and alpha-smooth muscle actin (SMA) proteins were assayed in quadriceps. Halo decreased fibrosis, collagen I and III expression, collagen protein and SMA content after 10 weeks treatment. Muscle-cell proliferation increased at 5 weeks, and HGF increased by 10 weeks treatment. Halo markedly improved cardiac function and respiratory function, and reduced damage and improved recovery from exercise. The overall impact of already-established dystrophy in cardiac and skeletal muscles was reduced. Marked improvements in vital-organ functions implicate Halo as a strong candidate drug to reduce morbidity and mortality in DMD.
