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Mechanical Activation of mTOR Signaling Requires a Phospholipase D‐Mediated Increase in Phosphatidic Acid
Author(s) -
Hornberger Troy Alan,
Chu Eric,
Haung Sharon,
Mak Eva,
Hsiung Jenny,
Chien Shu
Publication year - 2006
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.20.5.a818-b
Subject(s) - phospholipase d , pi3k/akt/mtor pathway , phosphatidic acid , pld2 , microbiology and biotechnology , phospholipase c , signal transduction , chemistry , p70 s6 kinase 1 , phosphoinositide phospholipase c , second messenger system , biochemistry , biology , phospholipid , membrane
Signaling by the mammalian target of rapamycin (mTOR) has been reported to be necessary for mechanical load‐induced growth of skeletal muscle. The mechanisms involved in the mechanical activation of mTOR signaling are not known, but several studies indicate that an atypical (nutrient and PI3K‐independent) mechanism is involved. Recently, a novel regulatory pathway for mTOR signaling involving phospholipase D (PLD) and the lipid second messenger phosphatidic acid (PA) was reported. In testing the role of the PLD /PA pathway in the mechanical activation of mTOR signaling, we demonstrated that both isoforms of PLD (PLD1 and PLD2) are localized to the z‐band of skeletal muscle (the primary site of mechanical force transmission). Mechanically loading skeletal muscle with passive stretch, ex vivo, promoted an increase in PLD activity, PA accumulation and mTOR signaling. Incubation with a PLD / phospholipase C (PLC) inhibitor, neomycin, blocked the mechanical activation of mTOR signaling. Inhibitors of PLC, intracellular calcium and protein kinase C (U73122, BAPTA‐AM and BIM, respectively) did not affect the mechanical activation of mTOR signaling. In contrast, inhibition of PLD with 1‐Butanol blocked the mechanical activation of mTOR signaling. These results suggest that the effect of neomycin was attributable to the inhibition PLD, but not PLC. Furthermore, both neomycin and 1‐Butanol blocked the mechanically induced increase in PA. Taken together, our results indicate that mechanical stimuli activate mTOR signaling through a PLD‐mediated increase in PA. Funded By: NIH R01HL64382 to S.C. and F32AR052240 to T.A.H.