THESIS
2010
xiv, 117 p. : ill. (some col.) ; 30 cm
Abstract
Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays important
roles during inflammation. However, its roles in myoblast differentiation and muscle
regeneration remain unexplored. We showed here that OSM potently inhibits myoblast
differentiation mainly by activating the JAK1/STAT1/STAT3 pathway. OSM downregulates
MEF2A, upregulates the expression of Id1 and Id2, and inhibits the transcriptional activity of
MyoD and MEF2. In addition, OSM also enhances the expression of STAT3 and OSM
receptor, which constitutes a positive feedback loop to further amplify OSM-induced
signaling. Moreover, we found that STAT1 physically associates with MEF2 and represses its
transcriptional activity, which could account for the OSM-mediated repression of MEF2.
Although undetecta...[
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Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays important
roles during inflammation. However, its roles in myoblast differentiation and muscle
regeneration remain unexplored. We showed here that OSM potently inhibits myoblast
differentiation mainly by activating the JAK1/STAT1/STAT3 pathway. OSM downregulates
MEF2A, upregulates the expression of Id1 and Id2, and inhibits the transcriptional activity of
MyoD and MEF2. In addition, OSM also enhances the expression of STAT3 and OSM
receptor, which constitutes a positive feedback loop to further amplify OSM-induced
signaling. Moreover, we found that STAT1 physically associates with MEF2 and represses its
transcriptional activity, which could account for the OSM-mediated repression of MEF2.
Although undetectable in normal muscles, OSM is rapidly induced upon injury and then
promptly downregulated just before the majority of myoblasts differentiate. Prolonged
expression of OSM in muscles compromised the regeneration process without affecting
myoblast proliferation, suggesting that OSM functions to prevent proliferating myoblasts
from premature differentiation during the early phase of muscle regeneration.
STAT3 is abundantly expressed in skeletal muscles and is involved in the proliferation of myoblasts. However, its role in vivo during muscle regeneration and hypertrophy has not
been explored mainly due to the early lethality o f STAT3
-/- mice. To overcome this problem,
STAT3 is specifically deleted in skeletal muscle by crossing STAT3 flox/flox mice with
Cre-expressing mice under the control of the pax7 or myf5 promoter. Both Cre lines resulted
in the deletion of STAT3 specifically and efficiently in skeletal muscles and primary
myoblasts. Next, we found that the loss of STAT3 leads to inhibition of satellite cells- mediated
compensatory muscle hypertrophy. In addition, MyoD and myogenin expression
was decreased in the STAT3 deficient mice. Further investigation of the primary myoblasts
from STAT3 deficient mice showed that the loss of STAT3 compromised the proliferation of
myoblasts and down-regulated c-Myc. Taken together, these results here indicated that
STAT3 is an essential regulator in satellite cells- mediated muscle hypertrophy.
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