Positive feedback in the Akt/mTOR pathway and its implications for growth signal progression in skeletal muscle cells: an analytical study.
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 homogeneous growth signals along the whole spatial extension of such long cells. Here we develop two biologically justified approximations which we study under the presence of four different initial conditions that describe different paradigms of IGF-1 receptor-induced Akt/mTOR activation. In first 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 defined 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 diffusion system revealed that diffusion filtered out high frequencies of spatially periodic initiator signals suggesting that the muscle cell is robust against fluctuations 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 differentiation and cell death in other spatially extended cells.
Hamilton Institute, National University of Ireland, Maynooth, Co. Kildare, Ireland.
Fernando
F
López-Caamal
Míriam R
MR
García
Richard H
RH
Middleton
Heinrich J
HJ
Huber
D000465:Algorithms; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology*; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
D009124:Muscle Proteins; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases