TIMP3: a physiological regulator of adult myogenesis.
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 TNFalpha-converting enzyme (TACE), acts as an on-off switch for myogenic differentiation by regulating autocrine TNFalpha 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 TNFalpha release, p38 MAPK activation, myogenic gene expression and myotube formation. TNFalpha supplementation at a physiological concentration rescues myoblast differentiation. Similarly, in the regenerating soleus, overexpression of TIMP3 impairs release of TNFalpha 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.
Liu
Huijie
H
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA.
Chen
Shuen-Ei
SE
Jin
Bingwen
B
Carson
James A
JA
Niu
Airu
A
Durham
William
W
Lai
Jian-Yang
JY
Li
Yi-Ping
YP
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D015870:Gene Expression; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D012038:Regeneration / Q000502:physiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse