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Inhibition of myogenic microRNAs 1, 133, and 206 by inflammatory cytokines links inflammation and muscle degeneration in adult inflammatory myopathies.
[inclusion body myositis]
The
molecular
basis
of
inflammatory
myopathies
such
as
dermatomyositis
(
DM
)
,
polymyositis
,
and
inclusion
body
myositis
,
which
share
the
characteristics
of
chronic
muscle
inflammation
and
skeletal
muscle
wasting
,
are
poorly
understood
.
As
such
,
effective
targeted
treatments
for
these
diseases
are
lacking
,
resulting
in
critical
unmet
medical
needs
for
these
devastating
diseases
.
The
purpose
of
this
study
was
to
identify
possible
new
targets
for
drug
development
by
exploring
the
mechanism
by
which
inflammation
may
play
a
role
in
the
pathology
of
the
inflammatory
myopathies
.
We
compared
expression
levels
of
inflammatory
cytokines
and
microRNAs
(
miRNAs
)
between
muscle
biopsy
samples
from
patients
with
inflammatory
myopathies
and
those
from
donors
without
myositis
.
In
vitro
human
and
mouse
model
systems
were
then
used
to
characterize
the
role
of
these
cytokines
and
microRNAs
on
myoblast-
to
-myocyte
differentiation
.
We
observed
increased
expression
of
inflammatory
cytokines
,
including
tumor
necrosis
factor
α
(
TNF
α
)
,
interferon-α
(
IFN
α
)
,
IFN
β
,
and
interleukin-
1
β
,
in
different
subtypes
of
inflammatory
myopathies
.
We
observed
decreased
expression
of
microRNA-
1
(
miR-
1
)
,
miR-
133
a
,
and
miR-
133
b
in
all
of
the
inflammatory
myopathy
subtypes
we
evaluated
,
as
well
as
decreased
expression
of
miR-
206
in
DM
;
these
miRNAs
are
essential
for
adult
skeletal
muscle
differentiation
and
maintenance
.
TNF
α
was
significantly
inversely
correlated
with
decreased
myogenic
miRNA
expression
in
the
inflammatory
myopathy
subtypes
.
In
mechanistic
studies
,
TNF
α
inhibited
the
expression
of
myogenic
miRNAs
and
suppressed
the
differentiation
of
C
2
C
12
myoblasts
to
myocytes
/
myotubes
in
an
NF-κB-dependent
manner
.
This
block
in
differentiation
by
TNF
α
was
relieved
by
overexpression
of
miR-
1
,
miR-
206
,
or
miR-
133
a
/
b
.
Taken
together
,
these
results
provide
a
new
mechanistic
link
between
the
action
of
proinflammatory
cytokines
and
the
degenerative
pathology
of
inflammatory
myopathies
,
and
suggest
therapeutic
approaches
for
these
diseases
.
Diseases
Validation
Diseases presenting
"and suggest therapeutic approaches for these diseases"
symptom
inclusion body myositis
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