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Positive Feedback in the AKT/mTOR pathway and its implications for growth signal progression in skeletal muscle cells: An analytical study

Lopez-Caamal, Fernando and García, Míriam R. and Middleton, Richard H. and Huber, Heinrich J. (2012) Positive Feedback in the AKT/mTOR pathway and its implications for growth signal progression in skeletal muscle cells: An analytical study. Journal of Theoretical Biology, 301. pp. 15-27. ISSN 0022-5193

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Abstract

The IGF-1 mediated AKT/mTOR pathway has been recently proposed as mediator of skeletal muscle growth and a positive feedback between Akt and mTOR was suggested to induce homogenous growth signals along the whole spatial extension of such long cells. Here we develop two biologically justied approximations which we study under the presence of four dierent initial conditions that describe dierent paradigms of IGF-1 receptor{induced Akt/mTOR activation. In rst scenario the activation of the feedback cascade was assumed to be mild or protein turnover considered to be high. In turn, in the second scenario the transcriptional regulation was assumed to maintain dened levels of inactive pro{enzymes. For both scenarios, we were able to obtain closed{form formulas for growth signal progression in time and space and found that a localised initial signal maintains its Gaussian shape, but gets delocalised and exponentially degraded. Importantly, mathematical treatment of the reaction diusion system revealed that diusion ltered out high frequencies of spatially periodic initiator signals suggesting that the muscle cell is robust against uctuations in spatial receptor expression or activation. However, neither scenario was consistent with the presence of stably travelling signal waves. Our study highlights the role of feedback loops in spatiotemporal signal progression and results can be applied to studies in cell proliferation, cell dierentiation and cell death in other spatially extended cells.

Item Type: Article
Additional Information: Preprint version of original published article. The definitive version of this article is available at http://www.sciencedirect.com/ DOI: http://dx.doi.org/10.1016/j.jtbi.2012.01.026
Keywords: AKT/mTOR; Skeletal muscle; Positive feedback; Protein activation; PDE; Analytical solutions;
Subjects: Science & Engineering > Hamilton Institute
Item ID: 3621
Depositing User: Miriam Garcia
Date Deposited: 01 May 2012 15:31
Journal or Publication Title: Journal of Theoretical Biology
Publisher: Elsevier
Refereed: No
URI:

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