mTOR at the nexus of nutrition, growth, ageing and disease

Liu, Grace Y.; Sabatini, David M.

doi:10.1038/s41580-019-0199-y

Cited by 1,746 publications

(1,949 citation statements)

References 291 publications

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“…Intriguingly, glucose deprivation-induced ULK1 phosphorylation is in part AMPK dependent and previous studies showed that ULK1 is a target of both AMPK and mTORC1 (refs. 2,27 ). Nevertheless, it is still not clear how ULK1 senses glucose starvation 28 .…”

Section: Ulk1 and The Trna Synthetase Lars1mentioning

confidence: 99%

How does mTOR sense glucose starvation? AMPK is the usual suspect

Leprivier

Rotblat

2020

Cell Death Discov.

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Glucose is a major requirement for biological life. Its concentration is constantly sensed at the cellular level, allowing for adequate responses to any changes of glucose availability. Such responses are mediated by key sensors and signaling pathway components that adapt cellular metabolism to glucose levels. One of the major hubs of these responses is mechanistic target of rapamycin (mTOR) kinase, which forms the mTORC1 and mTORC2 protein complexes. Under physiological glucose concentrations, mTORC1 is activated and stimulates a number of proteins and enzymes involved in anabolic processes, while restricting the autophagic process. Conversely, when glucose levels are low, mTORC1 is inhibited, in turn leading to the repression of numerous anabolic processes, sparing ATP and antioxidants. Understanding how mTORC1 activity is regulated by glucose is not only important to better delineate the biological function of mTOR, but also to highlight potential therapeutic strategies for treating diseases characterized by deregulated glucose availability, as is the case of cancer. In this perspective, we depict the different sensors and upstream proteins responsible of controlling mTORC1 activity in response to changes in glucose concentration. This includes the major energy sensor AMP-activated protein kinase (AMPK), as well as other independent players. The impact of such modes of regulation of mTORC1 on cellular processes is also discussed. Facts

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Section: Ulk1 and The Trna Synthetase Lars1mentioning

confidence: 99%

How does mTOR sense glucose starvation? AMPK is the usual suspect

Leprivier

Rotblat

2020

Cell Death Discov.

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“…TOR signalling is a key amino acid signalling pathway that is critical for growth, reproduction and lifespan. Because TOR activity increases with dietary protein levels, it has been implicated as mediating the detrimental effects on lifespan of high protein diets (Liu & Sabatini, 2020). This is supported by the fact that rapamycin, a pharmacological suppressor of TOR, has been shown to extend lifespan across numerous species, including Drosophila where it also suppresses egg production (Bjedov et al, 2010;Schinaman, Rana, Ja, Clark, & Walker, 2019;Scialò et al, 2015).…”

Section: Lifespan Extension By Rapamycin Depends On Dietary Cholestermentioning

confidence: 99%

A dietary sterol trade off determines lifespan responses to dietary restriction inDrosophila melanogaster

Zanco

Mirth

Sgrò

et al. 2020

Preprint

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Diet plays a significant role in maintaining lifelong health. In particular, lowering the dietary protein : carbohydrate ratio can improve lifespan. This has been interpreted as a direct effect of these macronutrients on physiology. Using Drosophila melanogaster, we show that the role of protein and carbohydrate on lifespan is indirect, acting by altering the partitioning of limiting amounts of dietary sterols between reproduction and lifespan. Shorter lifespans in flies fed on high protein : carbohydrate diets can be rescued by supplementing their food with cholesterol. Not only does this fundamentally alter the way we interpret the mechanisms of lifespan extension by dietary restriction, these data highlight the important principle that life histories can be affected by nutrient-dependent trade-offs that are indirect and independent of the nutrients (often macronutrients) that are the focus of study. This brings us closer to understanding the mechanistic basis of dietary restriction.

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“…5e). We them focused our attention on the two best-characterized mTORC1 targets, the ribosomal protein S6 [downstream target of the serine/threonine kinase p70S6K1 (S6K1)], and the eIF4Ebinding protein 1 (4E-BP1) [50,51]. Levels of phosphorylated form of S6 at S240/244 were increased in control group in TA muscle, but this effect was signi cantly lower in obestatin-treated animals (Fig.…”

Section: Resultsmentioning

confidence: 99%

Obestatin signaling controls Schwann cells and axonal transport to counteract neuromuscular synaptic loss in skeletal muscle

Camiña¹,

Sánchez‐Temprano²,

Leal‐López³

et al. 2020

Preprint

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Background. Injuries to the peripheral nerve system are common conditions, with broad spectrum of symptoms depending on the impaired nerves and severity of damage. Although peripheral nervous system retains a remarkable ability for regeneration, it is estimated that less than ten percent of patients fully recover function after nerve injury and the available treatments remain suboptimal. Here, we identify a role for the obestatin/GPR39 system in the regulation of the Schwann cell plasticity as well as in the preservation of neuromuscular synapses in the course of nerve repair. Methods. Utilizing a compression model of sciatic nerve injury, axonotmesis, we assessed the obestatin-related regenerative response in the peripheral nerve system. The role of the obestatin/GPR39 system was further evaluated on immortalized rat Schwann cells, IFRS1, and the model of neuronal differentiation, PC12 cells. The interactions between SCs and neurons was evaluated using a co-culture system that combine the SC cell line IFRS1 and the NGF-primed PC12. Results. Obestatin signaling directs proliferation and migration of Schwann cells that sustain axonal regrowth and later remyelinate regenerated axons. We provide evidence supporting the preservation of skeletal muscle by the maintenance of neuromuscular synapses through the axonal regulation of calpain-calpastatin proteolytic system. This encompasses the control of skeletal muscle homeostasis by regulation of the ubiquitin proteasome system and the autophagy machinery. Conclusions. These results provide important insights into how the obestatin/GPR39 system promotes nerve repair through integration of multiple molecular cues of neuron-Schwann cells crosstalk aimed to promote axon growth and guide axons back to their targets.

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mTOR at the nexus of nutrition, growth, ageing and disease

Cited by 1,746 publications

References 291 publications

How does mTOR sense glucose starvation? AMPK is the usual suspect

How does mTOR sense glucose starvation? AMPK is the usual suspect

A dietary sterol trade off determines lifespan responses to dietary restriction inDrosophila melanogaster

Obestatin signaling controls Schwann cells and axonal transport to counteract neuromuscular synaptic loss in skeletal muscle

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