PMID- 20237300
OWN - NLM
STAT- MEDLINE
DCOM- 20100615
LR  - 20200930
IS  - 1522-1490 (Electronic)
IS  - 0363-6119 (Linking)
VI  - 298
IP  - 6
DP  - 2010 Jun
TI  - Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is 
      associated with increased REDD1 expression in response to chronic hypoxia.
PG  - R1659-66
LID - 10.1152/ajpregu.00550.2009 [doi]
AB  - Although it is well established that chronic hypoxia leads to an inexorable loss 
      of skeletal muscle mass in healthy subjects, the underlying molecular mechanisms 
      involved in this process are currently unknown. Skeletal muscle atrophy is also 
      an important systemic consequence of chronic obstructive pulmonary disease 
      (COPD), but the role of hypoxemia in this regulation is still debated. Our 
      general aim was to determine the molecular mechanisms involved in the regulation 
      of skeletal muscle mass after exposure to chronic hypoxia and to test the 
      biological relevance of our findings into the clinical context of COPD. 
      Expression of positive and negative regulators of skeletal muscle mass were 
      explored 1) in the soleus muscle of rats exposed to severe hypoxia (6,300 m) for 
      3 wk and 2) in vastus lateralis muscle of nonhypoxemic and hypoxemic COPD 
      patients. In rodents, we observed a marked inhibition of the mammalian target of 
      rapamycin (mTOR) pathway together with a strong increase in regulated in 
      development and DNA damage response 1 (REDD1) expression and in its association 
      with 14-3-3, a mechanism known to downregulate the mTOR pathway. Importantly, 
      REDD1 overexpression in vivo was sufficient to cause skeletal muscle fiber 
      atrophy in normoxia. Finally, the comparative analysis of skeletal muscle in 
      hypoxemic vs. nonhypoxemic COPD patients confirms that hypoxia causes an 
      inhibition of the mTOR signaling pathway. We thus identify REDD1 as a negative 
      regulator of skeletal muscle mass during chronic hypoxia. Translation of this 
      fundamental knowledge into the clinical investigation of COPD shows the interest 
      to develop therapeutic strategies aimed at inhibiting REDD1.
FAU - Favier, Francois B
AU  - Favier FB
AD  - Universite de Lyon, Universite Jean Monnet, Laboratoire de Physiologie de 
      l'Exercice EA 4338, Saint Etienne, France.
FAU - Costes, Frederic
AU  - Costes F
FAU - Defour, Aurelia
AU  - Defour A
FAU - Bonnefoy, Regis
AU  - Bonnefoy R
FAU - Lefai, Etienne
AU  - Lefai E
FAU - Bauge, Stephane
AU  - Bauge S
FAU - Peinnequin, Andre
AU  - Peinnequin A
FAU - Benoit, Henri
AU  - Benoit H
FAU - Freyssenet, Damien
AU  - Freyssenet D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100317
PL  - United States
TA  - Am J Physiol Regul Integr Comp Physiol
JT  - American journal of physiology. Regulatory, integrative and comparative 
      physiology
JID - 100901230
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Atrophy/complications/metabolism/pathology
MH  - Down-Regulation
MH  - Humans
MH  - Hypoxia/complications/metabolism/pathology
MH  - Male
MH  - Mammals/metabolism
MH  - Muscle, Skeletal/*metabolism/pathology
MH  - Muscular Atrophy/etiology/*metabolism/pathology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Pulmonary Disease, Chronic Obstructive/complications/metabolism/pathology
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction
MH  - Sirolimus/*metabolism
EDAT- 2010/03/20 06:00
MHDA- 2010/06/16 06:00
CRDT- 2010/03/19 06:00
PHST- 2010/03/19 06:00 [entrez]
PHST- 2010/03/20 06:00 [pubmed]
PHST- 2010/06/16 06:00 [medline]
AID - 00550.2009 [pii]
AID - 10.1152/ajpregu.00550.2009 [doi]
PST - ppublish
SO  - Am J Physiol Regul Integr Comp Physiol. 2010 Jun;298(6):R1659-66. doi: 
      10.1152/ajpregu.00550.2009. Epub 2010 Mar 17.