PMID- 28130275
OWN - NLM
STAT- MEDLINE
DCOM- 20171004
LR  - 20211204
IS  - 1757-4684 (Electronic)
IS  - 1757-4676 (Print)
IS  - 1757-4676 (Linking)
VI  - 9
IP  - 3
DP  - 2017 Mar
TI  - Modulation of mTOR signaling as a strategy for the treatment of Pompe disease.
PG  - 353-370
LID - 10.15252/emmm.201606547 [doi]
AB  - Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic 
      processes in response to multiple extracellular and intracellular signals 
      including growth factors and nutrients. This serine/threonine kinase has long 
      been known as a critical regulator of muscle mass. The recent finding that the 
      decision regarding its activation/inactivation takes place at the lysosome 
      undeniably brings mTOR into the field of lysosomal storage diseases. In this 
      study, we have examined the involvement of the mTOR pathway in the 
      pathophysiology of a severe muscle wasting condition, Pompe disease, caused by 
      excessive accumulation of lysosomal glycogen. Here, we report the dysregulation 
      of mTOR signaling in the diseased muscle cells, and we focus on potential sites 
      for therapeutic intervention. Reactivation of mTOR in the whole muscle of Pompe 
      mice by TSC knockdown resulted in the reversal of atrophy and a striking removal 
      of autophagic buildup. Of particular interest, we found that the aberrant mTOR 
      signaling can be reversed by arginine. This finding can be translated into the 
      clinic and may become a paradigm for targeted therapy in lysosomal, metabolic, 
      and neuromuscular diseases.
CI  - (c) 2017 The Authors. Published under the terms of the CC BY 4.0 license.
FAU - Lim, Jeong-A
AU  - Lim JA
AD  - Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of 
      Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 
      Bethesda, MD, USA.
AD  - Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, 
      National Institutes of Health, Bethesda, MD, USA.
FAU - Li, Lishu
AU  - Li L
AUID- ORCID: 0000-0003-2133-6702
AD  - Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of 
      Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 
      Bethesda, MD, USA lishuli1@hotmail.com puertolr@mail.nih.gov rabenn@mail.nih.gov.
FAU - Shirihai, Orian S
AU  - Shirihai OS
AUID- ORCID: 0000-0001-8466-3431
AD  - Department of Medicine, Obesity and Nutrition Section, Evans Biomedical Research 
      Center, Boston University School of Medicine, Boston, MA, USA.
FAU - Trudeau, Kyle M
AU  - Trudeau KM
AD  - Department of Medicine, Obesity and Nutrition Section, Evans Biomedical Research 
      Center, Boston University School of Medicine, Boston, MA, USA.
FAU - Puertollano, Rosa
AU  - Puertollano R
AUID- ORCID: 0000-0002-1106-5489
AD  - Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, 
      National Institutes of Health, Bethesda, MD, USA lishuli1@hotmail.com 
      puertolr@mail.nih.gov rabenn@mail.nih.gov.
FAU - Raben, Nina
AU  - Raben N
AUID- ORCID: 0000-0001-9519-3535
AD  - Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of 
      Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 
      Bethesda, MD, USA lishuli1@hotmail.com puertolr@mail.nih.gov rabenn@mail.nih.gov.
LA  - eng
GR  - R01 DK099618/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PL  - England
TA  - EMBO Mol Med
JT  - EMBO molecular medicine
JID - 101487380
RN  - 94ZLA3W45F (Arginine)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Arginine/administration & dosage
MH  - Disease Models, Animal
MH  - Glycogen Storage Disease Type II/*physiopathology/therapy
MH  - Mice
MH  - Mice, Knockout
MH  - Muscles/pathology
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Treatment Outcome
PMC - PMC5331267
OTO - NOTNLM
OT  - mTOR
OT  - Pompe disease
OT  - autophagy
OT  - lysosomal storage disorders
OT  - myopathy
EDAT- 2017/01/29 06:00
MHDA- 2017/10/05 06:00
PMCR- 2017/03/01
CRDT- 2017/01/29 06:00
PHST- 2017/01/29 06:00 [pubmed]
PHST- 2017/10/05 06:00 [medline]
PHST- 2017/01/29 06:00 [entrez]
PHST- 2017/03/01 00:00 [pmc-release]
AID - emmm.201606547 [pii]
AID - EMMM201606547 [pii]
AID - 10.15252/emmm.201606547 [doi]
PST - ppublish
SO  - EMBO Mol Med. 2017 Mar;9(3):353-370. doi: 10.15252/emmm.201606547.