PMID- 24002653
OWN - NLM
STAT- MEDLINE
DCOM- 20140617
LR  - 20230620
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 27
IP  - 11
DP  - 2013 Nov
TI  - Smad3 induces atrogin-1, inhibits mTOR and protein synthesis, and promotes muscle 
      atrophy in vivo.
PG  - 1946-57
LID - 10.1210/me.2013-1194 [doi]
AB  - Myostatin, a member of the TGF superfamily, is sufficient to induce skeletal 
      muscle atrophy. Myostatin-induced atrophy is associated with increases in 
      E3-ligase atrogin-1 expression and protein degradation and decreases in 
      Akt/mechanistic target of rapamycin (mTOR) signaling and protein synthesis. 
      Myostatin signaling activates the transcription factor Smad3 (Small Mothers 
      Against Decapentaplegic), which has been shown to be necessary for 
      myostatin-induced atrogin-1 expression and atrophy; however, it is not known 
      whether Smad3 is sufficient to induce these events or whether Smad3 simply plays 
      a permissive role. Thus, the aim of this study was to address these questions 
      with an in vivo model. To accomplish this goal, in vivo transfection of plasmid 
      DNA was used to create transient transgenic mouse skeletal muscles, and our 
      results show for the first time that Smad3 expression is sufficient to stimulate 
      atrogin-1 promoter activity, inhibit Akt/mTOR signaling and protein synthesis, 
      and induce muscle fiber atrophy. Moreover, we propose that Akt/mTOR signaling is 
      inhibited by a Smad3-induced decrease in microRNA-29 (miR-29) expression and a 
      subsequent increase in the translation of phosphatase and tensin homolog (PTEN) 
      mRNA. Smad3 is also sufficient to inhibit peroxisome proliferator-activated 
      receptor-gamma coactivator-1alpha (PGC1alpha) promoter activity and to increase FoxO 
      (Forkhead Box Protein, Subclass O)-mediated signaling and the promoter activity 
      of plasminogen activator inhibitor 1 (PAI-1). Combined, this study provides the 
      first evidence that Smad3 is sufficient to regulate many of the events associated 
      with myostatin-induced atrophy and therefore suggests that Smad3 signaling may be 
      a viable target for therapies aimed at preventing myostatin-induced muscle 
      atrophy.
FAU - Goodman, Craig A
AU  - Goodman CA
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706. cgoodman2@wisc.edu.
FAU - McNally, Rachel M
AU  - McNally RM
FAU - Hoffmann, F Michael
AU  - Hoffmann FM
FAU - Hornberger, Troy A
AU  - Hornberger TA
LA  - eng
GR  - AR057347/AR/NIAMS NIH HHS/United States
GR  - R21 AR063256/AR/NIAMS NIH HHS/United States
GR  - AR063256/AR/NIAMS NIH HHS/United States
GR  - R56 AR057347/AR/NIAMS NIH HHS/United States
GR  - R01 AR057347/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130903
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Muscle Proteins)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Smad3 Protein)
RN  - 0 (Smad3 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 0 (Tripartite Motif Proteins)
RN  - EC 2.3.2.27 (Fbxo32 protein, mouse)
RN  - EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases)
RN  - EC 2.3.2.27 (Trim63 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (Pten protein, mouse)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Female
MH  - Gene Expression
MH  - Mice
MH  - Muscle Proteins/*genetics/metabolism
MH  - Muscle, Skeletal/metabolism/pathology
MH  - Muscular Atrophy/*metabolism
MH  - PTEN Phosphohydrolase/genetics/metabolism
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - SKP Cullin F-Box Protein Ligases/*genetics/metabolism
MH  - Signal Transduction
MH  - Smad3 Protein/*physiology
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Transcription Factors/genetics/metabolism
MH  - *Transcriptional Activation
MH  - Tripartite Motif Proteins
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
PMC - PMC3805852
EDAT- 2013/09/05 06:00
MHDA- 2014/06/18 06:00
PMCR- 2014/11/01
CRDT- 2013/09/05 06:00
PHST- 2013/09/05 06:00 [entrez]
PHST- 2013/09/05 06:00 [pubmed]
PHST- 2014/06/18 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - me.2013-1194 [pii]
AID - ME-13-1194 [pii]
AID - 10.1210/me.2013-1194 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2013 Nov;27(11):1946-57. doi: 10.1210/me.2013-1194. Epub 2013 Sep 
      3.