Exercise-induced metabolic reprogramming of NK cells: the mTORC1 pathway or adrenergic signalling

Abstract

The major aim of this study is to investigate the immunometabolic mechanisms of the antitumoral effects of NK cells in individuals engaged in lifelong exercise. The question that we propose to address is this proposal is: Can regular physical exercise create a metabolic and immune environment that suppresses tumorigenesis? We hypothesized that exercise-induced delay in immunosenescence, slowing down the inflammaging, may inhibit the cell transformation and tumour progression, an effect that might be mediated by immune cell-released molecules, including cytokines. In addition, the reduced risk of cancer has also been also linked to a myriad of acute and chronic effects of exercise on the immune system, including increased natural killer (NK)-cell cytotoxicity against tumours and possibly metabolic reprogramming of NK cells. As mTORC1 activation is required for NK cell function, we reasoned that mTORC1 is activated, via muscle-derived IL-6 and adrenaline secretion by physical exercise. Therefore, the repeat stimulation of the mTOR pathway in master athletes could promote the metabolic reprogramming of NK cells, creating a more efficient cellular and functional profile, with a potential antitumoral response. Thus, to test the requirement of mTORC1 for NK cell cytotoxic effector function, freshly NK isolated NK cells will be incubated in serum taken before and after an acute bout of exercise with the mTORC1 inhibitor rapamycin to analyse the IFN-³ and tumour-killing by NK cells. Moreover, the mTORC1 activation via the downstream phosphorylation of S6 (p-S6) by S6K will be evaluated by flow cytometry. It has already been shown that acute exercise affects the expression of miRNAs in NK cells. It is also assumed that miRNAs affect the metabolism. Therefore, the expression of specific miRNAs of NK cells will be analysed. To the end, an mechanistic approach, including a selective inhibition of potential mediators of the exercise effects will be done. (AU)