Abstract
Myogenic differentiation in adult muscle is normally suppressed and can be activated by myogenic cues in a subset of activated satellite cells. The switch mechanism that turns myogenesis on and off is not defined. In the present study, we demonstrate that tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of TNFα-converting enzyme (TACE), acts as an on-off switch for myogenic differentiation by regulating autocrine TNFα release. We observed that constitutively expressed TIMP3 is transiently downregulated in the satellite cells of regenerating mouse hindlimb muscles and differentiating C2C12 myoblasts. In C2C12 myoblasts, perturbing TIMP3 downregulation by overexpressing TIMP3 blocks TNFα release, p38 MAPK activation, myogenic gene expression and myotube formation. TNFα supplementation at a physiological concentration rescues myoblast differentiation. Similarly, in the regenerating soleus, overexpression of TIMP3 impairs release of TNFα and myogenic gene expression, and delays the formation of new fibers. In addition, downregulation of TIMP3 is mediated by the myogenesis-promoting microRNA miR-206. Thus, TIMP3 is a physiological regulator of myogenic differentiation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2914-2921 |
| Number of pages | 8 |
| Journal | Journal of Cell Science |
| Volume | 123 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2010 |
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Keywords
- Gene expression
- miR-206
- Muscle regeneration
- TNFα converting enzyme
ASJC Scopus subject areas
- Cell Biology
Cite this
TIMP3 : A physiological regulator of adult myogenesis. / Liu, Huijie; Chen, Shuen Ei; Jin, Bingwen; Carson, James A.; Niu, Airu; Durham, William; Lai, Jian Yang; Li, Yi Ping.
In: Journal of Cell Science, Vol. 123, No. 17, 01.09.2010, p. 2914-2921.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TIMP3
T2 - A physiological regulator of adult myogenesis
AU - Liu, Huijie
AU - Chen, Shuen Ei
AU - Jin, Bingwen
AU - Carson, James A.
AU - Niu, Airu
AU - Durham, William
AU - Lai, Jian Yang
AU - Li, Yi Ping
PY - 2010/9/1
Y1 - 2010/9/1
N2 - Myogenic differentiation in adult muscle is normally suppressed and can be activated by myogenic cues in a subset of activated satellite cells. The switch mechanism that turns myogenesis on and off is not defined. In the present study, we demonstrate that tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of TNFα-converting enzyme (TACE), acts as an on-off switch for myogenic differentiation by regulating autocrine TNFα release. We observed that constitutively expressed TIMP3 is transiently downregulated in the satellite cells of regenerating mouse hindlimb muscles and differentiating C2C12 myoblasts. In C2C12 myoblasts, perturbing TIMP3 downregulation by overexpressing TIMP3 blocks TNFα release, p38 MAPK activation, myogenic gene expression and myotube formation. TNFα supplementation at a physiological concentration rescues myoblast differentiation. Similarly, in the regenerating soleus, overexpression of TIMP3 impairs release of TNFα and myogenic gene expression, and delays the formation of new fibers. In addition, downregulation of TIMP3 is mediated by the myogenesis-promoting microRNA miR-206. Thus, TIMP3 is a physiological regulator of myogenic differentiation.
AB - Myogenic differentiation in adult muscle is normally suppressed and can be activated by myogenic cues in a subset of activated satellite cells. The switch mechanism that turns myogenesis on and off is not defined. In the present study, we demonstrate that tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of TNFα-converting enzyme (TACE), acts as an on-off switch for myogenic differentiation by regulating autocrine TNFα release. We observed that constitutively expressed TIMP3 is transiently downregulated in the satellite cells of regenerating mouse hindlimb muscles and differentiating C2C12 myoblasts. In C2C12 myoblasts, perturbing TIMP3 downregulation by overexpressing TIMP3 blocks TNFα release, p38 MAPK activation, myogenic gene expression and myotube formation. TNFα supplementation at a physiological concentration rescues myoblast differentiation. Similarly, in the regenerating soleus, overexpression of TIMP3 impairs release of TNFα and myogenic gene expression, and delays the formation of new fibers. In addition, downregulation of TIMP3 is mediated by the myogenesis-promoting microRNA miR-206. Thus, TIMP3 is a physiological regulator of myogenic differentiation.
KW - Gene expression
KW - miR-206
KW - Muscle regeneration
KW - TNFα converting enzyme
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UR - http://www.scopus.com/inward/citedby.url?scp=77956934525&partnerID=8YFLogxK
U2 - 10.1242/jcs.057620
DO - 10.1242/jcs.057620
M3 - Article
VL - 123
SP - 2914
EP - 2921
JO - Journal of Cell Science
JF - Journal of Cell Science
SN - 0021-9533
IS - 17
ER -