Abstract
The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression. Fiorillo et al. find that miRNAs in muscle promote variable dystrophin levels in muscular dystrophies. Dystrophin-targeting miRNAs reduce dystrophin and increase with disease severity. Innate inflammatory pathways induce miRNAs, whereas NFκB inhibition dampens induction. These events initiate a self-sustaining feedback loop, exacerbating disease progression. Thus, miRNA inhibition in dystrophic muscle could provide therapeutic targets.
| Original language | English |
|---|---|
| Pages (from-to) | 1678-1690 |
| Number of pages | 13 |
| Journal | Cell Reports |
| Volume | 12 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Sep 8 2015 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy. / Fiorillo, Alyson A.; Heier, Christopher R.; Novak, James S.; Tully, Christopher B.; Brown, Kristy J.; Uaesoontrachoon, Kitipong; Vila, Maria C.; Ngheim, Peter P.; Bello, Luca; Kornegay, Joe N.; Angelini, Corrado; Partridge, Terence A.; Nagaraju, Kanneboyina; Hoffman, Eric P.
In: Cell Reports, Vol. 12, No. 10, 08.09.2015, p. 1678-1690.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy
AU - Fiorillo, Alyson A.
AU - Heier, Christopher R.
AU - Novak, James S.
AU - Tully, Christopher B.
AU - Brown, Kristy J.
AU - Uaesoontrachoon, Kitipong
AU - Vila, Maria C.
AU - Ngheim, Peter P.
AU - Bello, Luca
AU - Kornegay, Joe N.
AU - Angelini, Corrado
AU - Partridge, Terence A.
AU - Nagaraju, Kanneboyina
AU - Hoffman, Eric P.
PY - 2015/9/8
Y1 - 2015/9/8
N2 - The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression. Fiorillo et al. find that miRNAs in muscle promote variable dystrophin levels in muscular dystrophies. Dystrophin-targeting miRNAs reduce dystrophin and increase with disease severity. Innate inflammatory pathways induce miRNAs, whereas NFκB inhibition dampens induction. These events initiate a self-sustaining feedback loop, exacerbating disease progression. Thus, miRNA inhibition in dystrophic muscle could provide therapeutic targets.
AB - The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression. Fiorillo et al. find that miRNAs in muscle promote variable dystrophin levels in muscular dystrophies. Dystrophin-targeting miRNAs reduce dystrophin and increase with disease severity. Innate inflammatory pathways induce miRNAs, whereas NFκB inhibition dampens induction. These events initiate a self-sustaining feedback loop, exacerbating disease progression. Thus, miRNA inhibition in dystrophic muscle could provide therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=84941180028&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84941180028&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.07.066
DO - 10.1016/j.celrep.2015.07.066
M3 - Article
AN - SCOPUS:84941180028
VL - 12
SP - 1678
EP - 1690
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 10
ER -