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Chronic paraplegia-induced muscle atrophy downregulates the mTOR/S6K1 signaling pathway.

Authors: Dreyer, HC  Glynn, EL  Lujan, HL  Fry, CS  DiCarlo, SE  Rasmussen, BB 
Citation: Dreyer HC, etal., J Appl Physiol. 2007 Sep 20;.
Pubmed: (View Article at PubMed) PMID:17885021
DOI: Full-text: DOI:10.1152/japplphysiol.00736.2007

Ribosomal S6 kinase 1 (S6K1) is a downstream component of the mammalian target of rapamycin (mTOR) signaling pathway and plays a regulatory role in translation initiation, protein synthesis, and muscle hypertrophy. AMP-activated protein kinase (AMPK) is a cellular energy sensor, a negative regulator of mTOR, and an inhibitor of protein synthesis. The purpose of this study was to determine if the hypertrophy/cell growth-associated mTOR pathway was downregulated during muscle atrophy associated with chronic paraplegia. Soleus muscle was collected from male Sprague-Dawley rats 10 weeks following complete T(4-5) spinal cord transection (Paraplegic) and from sham operated (Control) rats. We utilized immunoprecipitation and Western blotting techniques to measure upstream (AMPK, Akt/PKB) and downstream components of the mTOR signaling pathway (mTOR, S6K1, SKAR, 4EBP1 and eIF4G). Paraplegia was associated with significant soleus muscle atrophy (114+/-8mg vs. 240+/-13mg, P<0.05). There was a reduction in phosphorylation of mTOR, S6K1, and eIF4G (P<0.05) with no change in Akt/PKB or 4EBP1 (P>0.05). Total protein abundance of mTOR, S6K1, eIF2alpha and Akt/PKB was decreased, and increased for SKAR (P<0.05) while 4EBP1 and eIF4G did not change (P>0.05). S6K1 activity was significantly reduced in the Paraplegic group (P<0.05), however AMPKalpha2 activity was not altered (3.5+/-0.4 vs. 3.7+/-0.5 pmol.mg(-1).min(-1), Control vs. Paraplegic rats). We conclude that paraplegia induced muscle atrophy in rats is associated with a general downregulation of the mTOR signaling pathway. Therefore, in addition to upregulation of atrophy signaling during muscle wasting, downregulation of muscle cell growth/hypertrophy-associated signaling appears to be an important component of long-term muscle loss. Key words: muscle atrophy, spinal cord injury, rehabilitation, cell signaling.

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RGD Object Information
RGD ID: 1642984
Created: 2007-11-16
Species: All species
Last Modified: 2007-11-16
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.