Document Detail


The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb.
MedLine Citation:
PMID:  23193052     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Limb immobilization, limb suspension, and bed rest cause substantial loss of skeletal muscle mass, a phenomenon termed disuse atrophy. To acquire new knowledge that will assist in the development of therapeutic strategies for minimizing disuse atrophy, the present study was undertaken with the aim of identifying molecular mechanisms that mediate control of protein synthesis and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Male Sprague-Dawley rats were subjected to unilateral hindlimb immobilization for 1, 2, 3, or 7 days or served as nonimmobilized controls. Following an overnight fast, rats received either saline or L-leucine by oral gavage as a nutrient stimulus. Hindlimb skeletal muscles were extracted 30 min postgavage and analyzed for the rate of protein synthesis, mRNA expression, phosphorylation state of key proteins in the mTORC1 signaling pathway, and mTORC1 signaling repressors. In the basal state, mTORC1 signaling and protein synthesis were repressed within 24 h in the soleus of an immobilized compared with a nonimmobilized hindlimb. These responses were accompanied by a concomitant induction in expression of the mTORC1 repressors regulated in development and DNA damage responses (REDD) 1/2. The nutrient stimulus produced an elevation of similar magnitude in mTORC1 signaling in both the immobilized and nonimmobilized muscle. In contrast, phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) on Thr(229) and Thr(389) in response to the nutrient stimulus was severely blunted. Phosphorylation of Thr(229) by PDK1 is a prerequisite for phosphorylation of Thr(389) by mTORC1, suggesting that signaling through PDK1 is impaired in response to immobilization. In conclusion, the results show an immobilization-induced attenuation of mTORC1 signaling mediated by induction of REDD1/2 and defective p70S6K1 phosphorylation.
Authors:
Andrew R Kelleher; Scot R Kimball; Michael D Dennis; Rudolf J Schilder; Leonard S Jefferson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-27
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  304     ISSN:  1522-1555     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-16     Completed Date:  2013-03-12     Revised Date:  2014-01-23    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E229-36     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Enzyme Activation / drug effects
Hindlimb Suspension* / physiology
Leucine / pharmacology*
Male
Multiprotein Complexes
Muscle, Skeletal / drug effects,  metabolism*,  pathology
Nuclear Proteins / genetics,  metabolism*
Phosphorylation
Proteins / antagonists & inhibitors,  metabolism
Rats
Rats, Sprague-Dawley
Repressor Proteins / genetics,  metabolism*
Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
Signal Transduction / physiology
TOR Serine-Threonine Kinases
Transcription Factors / genetics,  metabolism*
Up-Regulation / drug effects,  genetics,  physiology
Grant Support
ID/Acronym/Agency:
DK-088416/DK/NIDDK NIH HHS; DK-15658/DK/NIDDK NIH HHS; R01 DK015658/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Multiprotein Complexes; 0/Nuclear Proteins; 0/Proteins; 0/RTP801 protein, rat; 0/Repressor Proteins; 0/SMHS1 protein, rat; 0/Transcription Factors; 0/mechanistic target of rapamycin complex 1; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 70-kDa; GMW67QNF9C/Leucine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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