PMID- 21669975
OWN - NLM
STAT- MEDLINE
DCOM- 20120417
LR  - 20211203
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 589
IP  - Pt 15
DP  - 2011 Aug 1
TI  - Novel events in the molecular regulation of muscle mass in critically ill 
      patients.
PG  - 3883-95
LID - 10.1113/jphysiol.2011.206193 [doi]
AB  - Critically ill patients experience marked skeletal muscle atrophy, but the 
      molecular mechanisms responsible for this are largely unresolved. Therefore, we 
      investigated key genes and proteins, identified from cell and animal studies to 
      control protein synthesis and breakdown, in vastus lateralis biopsy samples 
      obtained from 10 patients and 10 age- and sex-matched healthy controls. Muscle 
      cytokines IL-6 and TNF-alpha mRNA were higher in patients than in controls(6.5-fold; 
      P < 0.001 and 2-fold; P < 0.01). From the perspective of muscle protein 
      breakdown, muscle-specific E3-ligases (MAFbx and MuRF1) were higher in patients 
      at mRNA (4.5-fold; P < 0.05 and 2.5-fold; P < 0.05) and protein (5-fold; P < 
      0.001 and 4.5-fold; P < 0.001) level. Furthermore, 20S proteasome mRNA and 
      protein were higher in patients (5-fold; P < 0.001 and 2.5-fold; P < 0.01). 
      Cathepsin-L mRNA was 2-fold higher (P < 0.01), whilst calpain-3 mRNA(2-fold; P < 
      0.01) and protein (4-fold; P < 0.01)were lower inpatients. Another novel 
      observation was the 3-fold (P < 0.05) and 8.5-fold (P < 0.001) higher expression 
      of myostatin mRNA and protein in patients. Widespread dephosphorylation 
      (inactivation) of proteins regulating translation initiation factor activation 
      and protein synthesis (Akt1, GSK3alpha,beta, mTOR, p70S6K and 4E-BP1) was observed in 
      patients, which was paralleled by increases in their mRNAs. Finally, PDK4 mRNA 
      and protein was 2-fold (P < 0.05) and 2.6-fold (P < 0.01), respectively, higher 
      inpatients. In conclusion, we showed comprehensive alterations in molecular 
      events thought to reduce muscle mass and carbohydrate (CHO) oxidation in 
      critically ill patients. Nevertheless,these catabolic events were matched by a 
      cellular programme of anabolic restoration at the transcriptional level. This 
      shows a high molecular plasticity in the muscle of patients, and strategies to 
      preserve muscle mass and metabolic function should focus on maintaining Akt 
      phosphorylation and inhibiting myostatin expression.C
FAU - Constantin, Despina
AU  - Constantin D
AD  - School of Biomedical Sciences, Nottingham University Medical School, Queen's 
      Medical Centre, Nottingham NG7 2UH, UK. despina.constantin@nottingham.ac.uk
FAU - McCullough, Justine
AU  - McCullough J
FAU - Mahajan, Ravi P
AU  - Mahajan RP
FAU - Greenhaff, Paul L
AU  - Greenhaff PL
LA  - eng
GR  - G0501985/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110613
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Blood Glucose)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Interleukin-6)
RN  - 0 (Muscle Proteins)
RN  - 0 (Myostatin)
RN  - 0 (PDK4 protein, human)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.4.- (Cathepsins)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
CIN - J Physiol. 2011 Aug 15;589(Pt 16):3905-6. PMID: 21844005
CIN - J Physiol. 2011 Dec 15;589(Pt 24):5925-6. PMID: 22174144
MH  - Aged
MH  - Blood Glucose/metabolism
MH  - Carbohydrate Metabolism/physiology
MH  - Cathepsins/metabolism
MH  - Critical Illness
MH  - Eukaryotic Initiation Factors/metabolism
MH  - Female
MH  - Humans
MH  - Interleukin-6/metabolism
MH  - Male
MH  - Muscle Proteins/*genetics/*metabolism
MH  - Muscle, Skeletal/metabolism/*physiopathology
MH  - Muscular Atrophy/genetics/metabolism/*physiopathology
MH  - Myostatin/genetics/metabolism
MH  - Peptide Chain Initiation, Translational/genetics/physiology
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Protein Biosynthesis/genetics/physiology
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
MH  - RNA, Messenger/genetics
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Ubiquitin-Protein Ligases/metabolism
PMC - PMC3171892
EDAT- 2011/06/15 06:00
MHDA- 2012/04/18 06:00
PMCR- 2012/08/01
CRDT- 2011/06/15 06:00
PHST- 2011/06/15 06:00 [entrez]
PHST- 2011/06/15 06:00 [pubmed]
PHST- 2012/04/18 06:00 [medline]
PHST- 2012/08/01 00:00 [pmc-release]
AID - jphysiol.2011.206193 [pii]
AID - 10.1113/jphysiol.2011.206193 [doi]
PST - ppublish
SO  - J Physiol. 2011 Aug 1;589(Pt 15):3883-95. doi: 10.1113/jphysiol.2011.206193. Epub 
      2011 Jun 13.