Document Detail

Activation of calcium signaling through Trpv1 by nNOS and peroxynitrite as a key trigger of skeletal muscle hypertrophy.
MedLine Citation:
PMID:  23202294     Owner:  NLM     Status:  MEDLINE    
Skeletal muscle atrophy occurs in aging and pathological conditions, including cancer, diabetes and AIDS. Treatment of atrophy is based on either preventing protein-degradation pathways, which are activated during atrophy, or activating protein-synthesis pathways, which induce muscle hypertrophy. Here we show that neuronal nitric oxide synthase (nNOS) regulates load-induced hypertrophy by activating transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The overload-induced hypertrophy was prevented in nNOS-null mice. nNOS was transiently activated within 3 min after overload. This activation promoted formation of peroxynitrite, a reaction product of nitric oxide with superoxide, which was derived from NADPH oxidase 4 (Nox4). Nitric oxide and peroxynitrite then activated Trpv1, resulting in an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) that subsequently triggered activation of mammalian target of rapamycin (mTOR). Notably, administration of the TRPV1 agonist capsaicin induced hypertrophy without overload and alleviated unloading- or denervation-induced atrophy. These findings identify nitric oxide, peroxynitrite and [Ca(2+)](i) as the crucial mediators that convert a mechanical load into an intracellular signaling pathway and lead us to suggest that TRPV1 could be a new therapeutic target for treating muscle atrophy.
Naoki Ito; Urs T Ruegg; Akira Kudo; Yuko Miyagoe-Suzuki; Shin'ichi Takeda
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-02
Journal Detail:
Title:  Nature medicine     Volume:  19     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-08     Completed Date:  2013-03-06     Revised Date:  2013-08-06    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  101-6     Citation Subset:  IM    
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
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MeSH Terms
Antipruritics / pharmacology
Calcium / analysis
Calcium Signaling* / drug effects
Capsaicin / pharmacology
Cell Line
Hindlimb Suspension
Hypertrophy / metabolism,  pathology
Ion Transport / drug effects
Mice, Knockout
Muscle, Skeletal / metabolism,  pathology*
NADPH Oxidase / metabolism
Nitric Oxide / metabolism
Nitric Oxide Synthase Type I / metabolism*
Peroxynitrous Acid / metabolism*
Signal Transduction / drug effects
TRPV Cation Channels / metabolism*
Reg. No./Substance:
0/Antipruritics; 0/TRPV Cation Channels; 0/TRPV1 protein, mouse; 10102-43-9/Nitric Oxide; 14691-52-2/Peroxynitrous Acid; 404-86-4/Capsaicin; 7440-70-2/Calcium; EC Oxide Synthase Type I; EC protein, mouse; EC 1.6.-/Nox4 protein, mouse; EC Oxidase
Comment In:
Channels (Austin). 2013 May-Jun;7(3):221-4   [PMID:  23584166 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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