mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

Abstract

A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.

Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage

“…Moreover, a wide range of genes related to the p53, apoptosis, MAPK, mTOR, and FoxO pathways are regulated by Wnt/β-catenin signaling during early wound healing, but become far less responsive to Wnt later at the proliferative stage. Wnt/β-catenin signaling has been implicated in the regulation of proliferation and differentiation of various progenitor cells during tissue regeneration via controlling the p53, mTOR, and FoxO pathways ( Hirose et al, 2014 ; Peng et al, 2014 ; Maiese, 2015 ; Lund-Ricard et al, 2020 ). Besides, an intense crosstalk between the MAPK and Wnt signaling pathways has been deciphered in development, cancer, and regeneration ( Caverzasio and Manen, 2007 ; Bikkavilli et al, 2008 ; Zhang et al, 2014 ).…”

Salamander Insights Into Ageing and Rejuvenation

“…While little is known of how salamanders regulate nutrient sensing and its connection to their longevity, it is noteworthy that salamanders, as ectotherms, have inherently high levels of metabolic plasticity including thermal acclimation and hibernation/aestivation cycles, which may facilitate achieving metabolic states—at least temporarily — similar to those conducing to lifespan extension in mammals. Nevertheless, it is also worth noting that the aforementioned molecular regulators of anti-ageing are also involved in regenerative processes ( Lund-Ricard et al, 2020 ). Particularly, IGF1 and mTOR inhibition suppress blastema formation during zebrafish fin regeneration ( Hirose et al, 2014 ).…”

CrossTORC and WNTegration in Disease: Focus on Lymphangioleiomyomatosis

“…Perhaps most exciting would be the advances in stem cell research that would allow the regeneration of lung tissue or, indeed, the generation of the new adult lung [ 95 , 96 , 97 ]. However, since mTOR is central to cell-specific, spatial, and temporal control of tissue repair and regeneration, manipulation of this pathway will remain a major challenge for medical research [ 98 ].…”