PMID- 25020061
OWN - NLM
STAT- MEDLINE
DCOM- 20151117
LR  - 20220409
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 7
DP  - 2014
TI  - Fasting increases human skeletal muscle net phenylalanine release and this is 
      associated with decreased mTOR signaling.
PG  - e102031
LID - 10.1371/journal.pone.0102031 [doi]
LID - e102031
AB  - AIM: Fasting is characterised by profound changes in energy metabolism including 
      progressive loss of body proteins. The underlying mechanisms are however unknown 
      and we therefore determined the effects of a 72-hour-fast on human skeletal 
      muscle protein metabolism and activation of mammalian target of rapamycin (mTOR), 
      a key regulator of cell growth. METHODS: Eight healthy male volunteers were 
      studied twice: in the postabsorptive state and following 72 hours of fasting. 
      Regional muscle amino acid kinetics was measured in the forearm using amino acid 
      tracers. Signaling to protein synthesis and breakdown were assessed in skeletal 
      muscle biopsies obtained during non-insulin and insulin stimulated conditions on 
      both examination days. RESULTS: Fasting significantly increased forearm net 
      phenylalanine release and tended to decrease phenylalanine rate of disappearance. 
      mTOR phosphorylation was decreased by  approximately 50% following fasting, together with 
      reduced downstream phosphorylation of 4EBP1, ULK1 and rpS6. In addition, the 
      insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly 
      reduced after fasting indicating insulin resistance in this part of the signaling 
      pathway. Autophagy initiation is in part regulated by mTOR through ULK1 and 
      fasting increased expression of the autophagic marker LC3B-II by  approximately 30%. p62 is 
      degraded during autophagy but was increased by  approximately 10% during fasting making 
      interpretation of autophagic flux problematic. MAFbx and MURF1 ubiquitin ligases 
      remained unaltered after fasting indicating no change in protesomal protein 
      degradation. CONCLUSIONS: Our results show that during fasting increased net 
      phenylalanine release in skeletal muscle is associated to reduced mTOR activation 
      and concomitant decreased downstream signaling to cell growth.
FAU - Vendelbo, Mikkel Holm
AU  - Vendelbo MH
AD  - Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 
      Aarhus, Denmark.
FAU - Moller, Andreas Buch
AU  - Moller AB
AD  - Research Laboratory for Biochemical Pathology, Aarhus University Hospital, 
      Aarhus, Denmark.
FAU - Christensen, Britt
AU  - Christensen B
AD  - Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 
      Aarhus, Denmark.
FAU - Nellemann, Birgitte
AU  - Nellemann B
AD  - Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 
      Aarhus, Denmark.
FAU - Clasen, Berthil Frederik Forrest
AU  - Clasen BF
AD  - Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 
      Aarhus, Denmark; Research Laboratory for Biochemical Pathology, Aarhus University 
      Hospital, Aarhus, Denmark.
FAU - Nair, K Sreekumaran
AU  - Nair KS
AD  - Division of Endocrinology, Endocrine Research Unit, Mayo Clinic, Rochester, 
      Minnesota, United States of America.
FAU - Jorgensen, Jens Otto Lunde
AU  - Jorgensen JO
AD  - Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 
      Aarhus, Denmark.
FAU - Jessen, Niels
AU  - Jessen N
AD  - Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 
      Aarhus, Denmark; Research Laboratory for Biochemical Pathology, Aarhus University 
      Hospital, Aarhus, Denmark; Department of Molecular Medicine, Aarhus University 
      Hospital, Aarhus, Denmark.
FAU - Moller, Niels
AU  - Moller N
AD  - Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 
      Aarhus, Denmark.
LA  - eng
GR  - U24 DK100469/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20140714
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amino Acids)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 42HK56048U (Tyrosine)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acids/blood
MH  - Analysis of Variance
MH  - Blotting, Western
MH  - Cross-Over Studies
MH  - Energy Metabolism/*physiology
MH  - Fasting/*physiology
MH  - Fatty Acids, Nonesterified/blood
MH  - Gas Chromatography-Mass Spectrometry
MH  - Glucagon/blood
MH  - Humans
MH  - Male
MH  - Muscle, Skeletal/*metabolism
MH  - Phenylalanine/*metabolism
MH  - Radioimmunoassay
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tyrosine/metabolism
PMC - PMC4096723
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/07/16 06:00
MHDA- 2015/11/18 06:00
PMCR- 2014/07/14
CRDT- 2014/07/15 06:00
PHST- 2013/12/15 00:00 [received]
PHST- 2014/06/13 00:00 [accepted]
PHST- 2014/07/15 06:00 [entrez]
PHST- 2014/07/16 06:00 [pubmed]
PHST- 2015/11/18 06:00 [medline]
PHST- 2014/07/14 00:00 [pmc-release]
AID - PONE-D-13-52840 [pii]
AID - 10.1371/journal.pone.0102031 [doi]
PST - epublish
SO  - PLoS One. 2014 Jul 14;9(7):e102031. doi: 10.1371/journal.pone.0102031. 
      eCollection 2014.