Regulation of mTOR Signalling by Branched-Chain Amino Acids: Relevance to Research on HMB and Energy Metabolism and Neurodegenerative Diseases

This article [Nobukuni et al., 2005: (http://www.pnas.org/content/102/40/14238.full)(http://www.ncbi.nlm.nih.gov/pubmed/16176982?dopt=Abstract)] discusses some mechanisms whereby branched-chain amino acids (BCAA's) (or, by extension, the metabolites of BCAA's, such as 3-hydroxyisovalerate/HMB) can activate mTOR-dependent signalling. It sounds like they're saying that the repletion of cells with free amino acids augments mTOR-dependent signalling through a rapamycin-resistant pathway that's similar to or overlaps with an insulin-stimulated, rapamycin-resistant signalling pathway. The only other thing I gleaned from a quick glance at the article is that changes in aminoacyl-tRNA levels or in the acetylation of aminoacyl-tRNA's, such as histidyl-tRNA, do not appear to mediate the BCAA-dependent increases in mTOR activity. Rather, the authors argued that the BCAA-dependent changes in mTOR activity had been dependent on the levels of intracellular, free amino acids.

This article is interesting and has been cited 172 times, but I guess I'd like to know how any one of the changes in protein-protein interactions might interact with energy metabolism, overall, in the cell. I know that's a tall order, but the importance of all of those protein-protein interactions might be rapidly nullified by changes in the availabilities of energy substrates, etc. In my opinion, one problem with research in molecular biology and even with research in cultured cells, in general, as opposed to research that gives some attention to metabolism, is the implicit assumption that cells, in vivo, will be supplied with the kinds of perfectly-abundant concentrations of energy substrates that cells in culture are provided with. I think this is really important and bears on research in stem cell biology, for example. There's a lot of potential in that area, when one looks into the future, but cells in the brain don't provide any indication, such as might be visible on an MRI or that might cause symptoms in a person, that they are dying in large numbers. It's only after the cells have been dying for 20 or 30 years and have become dramatically decreased in numbers that a person might, for example, develop obvious symptoms of Parkinsonism. That occurs normally during aging, but the assumption should be, in my opinion, that cells are unlikely to be able to meet their energy requirements in vivo. Varying the supplies of different substrates in a cell culture medium would require a lot of effort, and the extra effort probably couldn't be justified if researchers were already investigating mTOR signalling or other intracellular signalling pathways. But I think the development of some of these prodrug delivery methods, for delivering physiological compounds, should be given a higher priority than people are giving it. In the face of hypoxia or glucose deprivation, giving attention to protein-protein interactions can be like shuffling cards or dealing all the players a new hand of cards while all the players are suffocating, as the the oxygen is being sucked out of the room.