title: Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle.
abstract: Maintenance of skeletal muscle mass relies on the dynamic balance between anabolic and catabolic processes and is important for motility, systemic energy homeostasis, and viability. We identified direct target genes of the glucocorticoid receptor (GR) in skeletal muscle, i.e., REDD1 and KLF15. As well as REDD1, KLF15 inhibits mTOR activity, but via a distinct mechanism involving BCAT2 gene activation. Moreover, KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1 genes and negatively modulates myofiber size. Thus, GR is a liaison involving a variety of downstream molecular cascades toward muscle atrophy. Notably, mTOR activation inhibits GR transcription function and efficiently counteracts the catabolic processes provoked by glucocorticoids. This mutually exclusive crosstalk between GR and mTOR, a highly coordinated interaction between the catabolic hormone signal and the anabolic machinery, may be a rational mechanism for fine-tuning of muscle volume and a potential therapeutic target for muscle wasting.
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Noritada
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Ito
authors.forename: Takako
authors.initials: T
authors.lastname: Maruyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Sin-ichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Jun
authors.initials: J
authors.lastname: Nakae
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tagata
authors.forename: Shinobu
authors.initials: S
authors.lastname: Nishitani
authors.forename: Kenji
authors.initials: K
authors.lastname: Takehana
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C000632146:Ddit4 protein, rat; C520013:Klf15 protein, rat; D051741:Kruppel-Like Transcription Factors; D009124:Muscle Proteins; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases