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Mammalian Target of Rapamycin Impairs Insulin’s Ability to Promote Protein Kinase B Phosphorylation in Isolated Rat Skeletal Muscle
Author(s) -
Reynolds Thomas H.,
Phelps Charlie
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a835-b
The mammalian target of rapamycin (mTOR) is a nutrient sensitive Ser/Thr kinase that has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. The purpose of the present study was to determine if activating mTOR signaling decreases insulin’s ability to promote the phosphorylation of protein kinase B (PKB) on Thr 308 and Ser 473 in rat skeletal muscle. Epitrochlearis muscles were isolated intact from male Wistar rats (~75 g) and incubated in vitro in the presence or absence of 750 uU/ml of insulin (I) or I and 2.5X DMEM amino acids (IA). In some experiments muscles were exposed to 100 nM rapamycin (R), a highly specific inhibitor of mTOR. We demonstrate that incubating muscles with IA, but not I alone, fully activated mTOR signaling as evidenced by the phosphorylation of S6K on Thr 389 , a phosphorylation site that is a well‐established target of mTOR’s kinase activity. Activating mTOR signaling with IA reduced insulin’s ability to promote the phosphorylation of PKB on Thr 308 by 55% (P = 0.003) and on Ser 473 by 28% (P = 0.01). The ability if IA to inhibit PKB phosphorylation was completely abolished by R treatment, indicating that mTOR mediated this process. Since mTOR is thought to produce insulin resistance by targeting IRS‐1 for degradation, we assessed whether or not activating mTOR signaling would result in a lower abundance of IRS‐1. Preliminary experiments demonstrate a trend (p = 0.178) for lower IRS‐1 levels in muscles incubated with IA compare to muscles incubated with I alone or with IAR. In summary, activating mTOR signaling with IA decreases insulin’s ability to promote the phosphorylation of PKB in isolated rat epitrochlearis muscle. The mTOR mediated impairment of PKB phosphorylation may be associated with reduced IRS‐1 levels and skeletal muscle insulin resistance.

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