Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse by halofuginone.
Fibrosis is a known feature of dystrophic muscles, particularly the diaphragm, in the mdx mouse. In this study we evaluated the effect of halofuginone, a collagen synthesis inhibitor, on collagen synthesis in various muscles of young wild-type (C57/BL/6J) and mdx mice. Halofuginone prevented the age-dependent increase in collagen synthesis in the diaphragms of mdx with no effect on wild-type mice (n = 5 for each time point). This was associated with a decrease in the degenerated areas and number of central nuclei. Halofuginone also inhibited collagen synthesis in cardiac muscle. Moreover, enhanced motor coordination, balance and improved cardiac muscle function were observed implying reduced muscle injury. Halofuginone inhibited Smad3 phosphorylation downstream of TGFbeta in the diaphragm and cardiac muscles, in C2 cell line and in primary mouse myoblast cultures representing various muscular dystrophies. We suggest that via its effect on Smad3 phosphorylation, halofuginone inhibits muscle fibrosis and improves cardiac and skeletal muscle functions in mdx mice.
Turgeman
Tidhar
T
Institute of Animal Sciences, The Volcani Center, P.O. Box 6, Bet Dagan 50250, Israel.
Hagai
Yosey
Y
Huebner
Kyla
K
Jassal
Davinder S
DS
Anderson
Judy E
JE
Genin
Olga
O
Nagler
Arnon
A
Halevy
Orna
O
Pines
Mark
M
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009132:Muscles / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology*; D045442:Rotarod Performance Test / Q000379:methods; D051900:Smad3 Protein / Q000378:metabolism
D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D052999:Quinazolinones; D051900:Smad3 Protein; D003094:Collagen; C010176:halofuginone