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פותח על ידי קלירמאש פתרונות בע"מ -
Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone
Year:
2013
Source of publication :
Histology and Histopathology
Authors :
גנין, אולגה
;
.
לוי, אשרת
;
.
משה, איתי
;
.
פימה, יניב
;
.
פינס, מרק
;
.
Volume :
28
Co-Authors:
Halevy, O., Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot, Israel
Genin, O., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Barzilai-Tutsch, H., Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot, Israel
Pima, Y., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Levi, O., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Moshe, I., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Pines, M., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Facilitators :
From page:
211
To page:
226
(
Total pages:
16
)
Abstract:
Summary. Absence of, or loss-of-function mutations in the dysferlin gene (dysf) result in dysferlinopathy, characterized by increased muscle inflammation, collagen deposition and deterioration in muscle function. We evaluated halofuginone efficacy in improving muscle histopathology in mice with deleted dysf transmembrane domain. Quadriceps sublumbar and longissimus muscles of 9-month-old dysf-/- mice treated with halofuginone for 4 months exhibited a reduction in centrally-nucleated myofibers, inflammatory infiltrates and collagen content. Late onset of dysferlinopathy makes it ideal for evaluating the efficacy of early treatments on late outcome. The dysf-/- mice were treated with halofuginone for 3 to 4 months starting at 1, 5 or 9 months of age, and quadricep muscle histopathology was evaluated at 12 months. Collagen content and number of centrally nucleated myofibers decreased after early halofuginone treatment, administered when myofibers with central nuclei and inflammatory infiltrates are evident, but there was almost no fibrosis. When administered at the beginning of fibrosis it resulted in a further decrease in the number of centrally-nucleated myofibers with no additional decrease in collagen levels. Cardiac fibrosis was almost completely abolished following early halofuginone treatment. Halofuginone inhibited Smad3 phosphorylation and its translocation to the nucleus and increased the activity of matrix metalloproteinases 9 and 2 responsible for resolution of pre-existing collagen. Macrophage and myofibroblast invasion into the dystrophic muscle at the site of myofibers with central nuclei was inhibited by halofuginone. These results suggest that early halofuginone treatment can prevent the late outcome of dysferlinopathy and can cause resolution of the established fibrosis when administered at later stages.
Note:
Related Files :
Animal
Animals
Dysferlinopathies
Genetics
Male
metabolism
mice
Pathology
quinazolinone derivative
עוד תגיות
תוכן קשור
More details
DOI :
Article number:
0
Affiliations:
Database:
סקופוס
Publication Type:
מאמר
;
.
Language:
אנגלית
Editors' remarks:
ID:
27315
Last updated date:
02/03/2022 17:27
Creation date:
17/04/2018 00:29
You may also be interested in
Scientific Publication
Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone
28
Halevy, O., Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot, Israel
Genin, O., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Barzilai-Tutsch, H., Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot, Israel
Pima, Y., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Levi, O., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Moshe, I., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Pines, M., Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone
Summary. Absence of, or loss-of-function mutations in the dysferlin gene (dysf) result in dysferlinopathy, characterized by increased muscle inflammation, collagen deposition and deterioration in muscle function. We evaluated halofuginone efficacy in improving muscle histopathology in mice with deleted dysf transmembrane domain. Quadriceps sublumbar and longissimus muscles of 9-month-old dysf-/- mice treated with halofuginone for 4 months exhibited a reduction in centrally-nucleated myofibers, inflammatory infiltrates and collagen content. Late onset of dysferlinopathy makes it ideal for evaluating the efficacy of early treatments on late outcome. The dysf-/- mice were treated with halofuginone for 3 to 4 months starting at 1, 5 or 9 months of age, and quadricep muscle histopathology was evaluated at 12 months. Collagen content and number of centrally nucleated myofibers decreased after early halofuginone treatment, administered when myofibers with central nuclei and inflammatory infiltrates are evident, but there was almost no fibrosis. When administered at the beginning of fibrosis it resulted in a further decrease in the number of centrally-nucleated myofibers with no additional decrease in collagen levels. Cardiac fibrosis was almost completely abolished following early halofuginone treatment. Halofuginone inhibited Smad3 phosphorylation and its translocation to the nucleus and increased the activity of matrix metalloproteinases 9 and 2 responsible for resolution of pre-existing collagen. Macrophage and myofibroblast invasion into the dystrophic muscle at the site of myofibers with central nuclei was inhibited by halofuginone. These results suggest that early halofuginone treatment can prevent the late outcome of dysferlinopathy and can cause resolution of the established fibrosis when administered at later stages.
Scientific Publication
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