Publication: Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone
Authors
Halevy, Orna ; Genin, Olga ; Barzilai-Tutsch, Hila ; Pima, Yaniv ; Levi, Oshrat ; Moshe, Itai ; Pines, Mark
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Publisher
F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología
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DOI
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info:eu-repo/semantics/article
Description
Abstract
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.
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Citation
Histology and Histopathology, vol. 28, nº 2, (2013)
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