Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone.
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 alpha-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.
Huebner
Kyla D
KD
Dept. of Biological Sciences, Faculty of Science, Univ. of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada.
Jassal
Davinder S
DS
Halevy
Orna
O
Pines
Mark
M
Anderson
Judy E
JE
D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010807:Physical Endurance / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D052097:Quadriceps Muscle / Q000187:drug effects / Q000473:pathology; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use; D015656:Respiratory Mechanics / Q000187:drug effects; D012420:Running; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D000199:Actins; D024042:Collagen Type I; D024061:Collagen Type III; D017228:Hepatocyte Growth Factor; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D052999:Quinazolinones; C498862:Acta2 protein, rat; C010176:halofuginone