Publication: Halofuginone and muscular dystrophy
Authors
Pines, Mark ; Halevy, Orna
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Publisher
Murcia: F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Muscular dystrophies (MDs) include
different inherited diseases that all result in progressive
muscle degeneration, impaired locomotion and often
premature death. The major focus of MD research has
been on alleviating the primary genetic deficit - using
gene therapy and myoblast-transfer approaches to
promote expression of the deficient or mutated genes in
the muscle fibers. Although promising, these approaches
have not yet entered into clinical practice and
unfortunately for MD patients, there is currently no cure.
Thus, the development of complementary and supportive
therapies that slow disease progression and improve
patients' quality of life is critically important. The main
features of MDs are sarcolemmal instability and
increased myofiber vulnerability to mechanical stress,
resulting in myofiber degeneration. Fibrosis, with
progressive replacement of muscle tissue, is a prominent
feature in some MDs, preventing complete regeneration
and hampering muscle functions. TGFß is the leading
candidate for activating fibroblasts and eliciting
overproduction of extracellular matrix (ECM) proteins.
Halofuginone, an inhibitor of Smad3 phosphorylation
downstream of TGFß signaling, inhibits the activation of
fibroblasts and their ability to synthesize ECM,
regardless of their origin or location. In animal models
of MDs with prominent muscle fibrosis, halofuginone
treatment has resulted in both prevention of collagen
production in young animals and resolution of
established fibrosis in older ones: the reduction in
muscle collagen content was associated with improved
muscle histopathology and major improvements in
muscle function. Recently, these halofuginonedependent
improvements were also observed in MD
with minor fibrosis involvement, probably due to a
direct effect of halofuginone on muscle cells, resulting in
myotube fusion that is dependent on Akt and MAPK pathway activation. In summary, halofuginone improves
muscle histopathology and muscle functions in various
MDs, via inhibition of muscle fibrosis on the one hand,
and increased myotube fusion on the other.
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