PMID- 32893874
OWN - NLM
STAT- MEDLINE
DCOM- 20210301
LR  - 20220531
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Linking)
VI  - 598
IP  - 23
DP  - 2020 Dec
TI  - Rapamycin and mTORC2 inhibition synergistically reduce contraction-stimulated 
      muscle protein synthesis.
PG  - 5453-5466
LID - 10.1113/JP280528 [doi]
AB  - KEY POINTS: Muscle contractions increase protein synthesis in a mechanistic 
      target of rapamycin (mTOR)-dependent manner, yet it is unclear which/how mTOR 
      complexes regulate muscle protein synthesis. We investigated the requirement of 
      mTOR Complex 2 (mTORC2) in contraction-stimulated muscle protein synthesis. 
      mTORC2 inhibition by muscle-specific Rictor knockout (Rictor mKO) did not prevent 
      contraction-induced muscle protein synthesis. Rapamycin prevented 
      contraction-induced muscle protein synthesis in Rictor mKO but not wild-type 
      mice. ABSTRACT: Protein synthesis increases following muscle contractions. 
      Previous studies have shown that inhibition of the mechanistic target of 
      rapamycin complex 1 (mTORC1) suppresses the early but not late muscle protein 
      synthesis response, while inhibition of both mTORC1 and mTORC2 abolishes the two 
      effects. Therefore, we hypothesized that mTORC2 regulates muscle protein 
      synthesis following muscle contractions. To test this, we investigated the effect 
      of mTORC2 inhibition by mouse muscle-specific Rictor knockout (Rictor mKO) on 
      muscle protein synthesis 3 h after contraction. The right gastrocnemius muscles 
      of Rictor mKO and wild-type (WT) mice were isometrically contracted using 
      percutaneous electrical stimulation, while the left gastrocnemius muscles served 
      as controls. Vehicle or the mTORC1 inhibitor rapamycin (1.5 mg/kg) was injected 
      intraperitoneally 1 h before contraction. Treatment of WT mice with rapamycin and 
      Rictor mKO lowered protein synthesis in general, but the response to contractions 
      was intact 3 h after contractions in both conditions. Rapamycin treatment in 
      Rictor mKO mice prevented contraction-stimulated muscle protein synthesis. 
      Notably, signalling traditionally associated with mTORC1 was increased by muscle 
      contractions despite rapamycin treatment. In rapamycin-treated Rictor mKO mice, 
      the same mTORC1 signalling was blocked following contractions. Our results 
      indicate that although neither rapamycin-sensitive mTOR/mTORC1 nor mTORC2 is 
      necessary for contraction-induced muscle protein synthesis, combined inhibition 
      of rapamycin-sensitive mTOR/mTORC1 and mTORC2 synergistically inhibits 
      contraction-induced muscle protein synthesis.
CI  - (c) 2020 The Authors. The Journal of Physiology (c) 2020 The Physiological Society.
FAU - Ogasawara, Riki
AU  - Ogasawara R
AUID- ORCID: 0000-0002-2600-1613
AD  - Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, 
      Nagoya, Japan.
AD  - Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, 
      University of Copenhagen, Denmark.
FAU - Knudsen, Jonas R
AU  - Knudsen JR
AUID- ORCID: 0000-0002-5471-491X
AD  - Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, 
      University of Copenhagen, Denmark.
AD  - Laboratory of Microsystems 2, Ecole Polytecgnique Federale de Lausanne, 
      Switzerland.
FAU - Li, Jingwen
AU  - Li J
AUID- ORCID: 0000-0003-1475-5335
AD  - Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, 
      University of Copenhagen, Denmark.
FAU - Ato, Satoru
AU  - Ato S
AUID- ORCID: 0000-0002-0667-8790
AD  - Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, 
      Nagoya, Japan.
FAU - Jensen, Thomas E
AU  - Jensen TE
AUID- ORCID: 0000-0001-6139-8268
AD  - Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, 
      University of Copenhagen, Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200923
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Muscle Proteins)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - Mice
MH  - *Muscle Contraction
MH  - Muscle Proteins/genetics
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - *Sirolimus/pharmacology
OTO - NOTNLM
OT  - cell signalling
OT  - exercise
OT  - mTORC1
OT  - mTORC2
OT  - protein translation
EDAT- 2020/09/08 06:00
MHDA- 2021/03/02 06:00
CRDT- 2020/09/07 08:39
PHST- 2020/08/10 00:00 [received]
PHST- 2020/08/24 00:00 [accepted]
PHST- 2020/09/08 06:00 [pubmed]
PHST- 2021/03/02 06:00 [medline]
PHST- 2020/09/07 08:39 [entrez]
AID - 10.1113/JP280528 [doi]
PST - ppublish
SO  - J Physiol. 2020 Dec;598(23):5453-5466. doi: 10.1113/JP280528. Epub 2020 Sep 23.