Overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy and the kinase activity of mTOR is necessary for this event

Avila G.

Avruch J.

Baar K.

Bodine S. C.

Brown E. J.

Carl-Henrik Heldin

Carter M. S.

Craig A. Goodman

Danielle M. Mabrey

Davies S. P.

Efeyan A.

Erbay E.

Frost R. A.

Garami A.

Ge Y.

Guertin D. A.

Hamilton D. L.

Hannah C. Lincoln

Hawkins P. T.

Herningtyas E. H.

Hornberger T. A.

Hresko R. C.

Isotani S.

Izumiya Y.

Jie Chen

John W. Frey

Jung C. H.

Kline W. O.

Laviola L.

Lee R. C.

Lewis M. I.

Li Y.

Mahoney S. J.

Man Hing Miu

Miyazaki M.

Nader G. A.

O'Neil T. K.

Oshiro N.

Osman B.

Pallafacchina G.

Park I. H.

Peterson R. T.

Price D. J.

Rommel C.

Sandri M.

Sarbassov D. D.

Sato T.

Seguin R.

Sun Y.

Tee A. R.

Troy A. Hornberger

Tsang C. K.

Vanhaesebroeck B.

Wang T.

Wu Y.

Yang Q.

Yejing Ge

English

PubMed

It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hyper-trophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confer

CiteSeerX

A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

Goodman, Craig

Miu, Man Hing

Frey, John W

Mabrey, Danielle M

Lincoln, Hannah C

Ge, Yejing

Chen, Jie

Hornberger, Troy A

Victoria University Eprints Repository

A phosphatidylinositol 3-kinase/protein kinase B-independent activation of mammalian target of rapamycin signaling is sufficient to induce skeletal muscle hypertrophy

It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event

Goodman, CA

Miu, MH

Frey, JW

Mabrey, DM

Lincoln, HC

Ge, Y

Chen, J

Hornberger, TA

University of Melbourne Institutional Repository

Molecular Biology of the Cell

Name not available

Victoria University Institutional Repository (VUIR)

Crossref

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ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/64/97/zmk3258.PMC2938390.pdf

A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

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