Karppinen, P. | Search bioRxiv

bioRxiv2023

A 2-Hydroxybutyrate-mediated feedback loop regulates muscular fatigue

The metabolite 2-hydroxybutyrate (2HB) is produced by skeletal muscle acutely during exercise and persists for several hours in the blood post-exertion. We show here that 2HB directly inhibits branched- chain aminotransferase enzymes, and that this inhibition in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBP{beta} mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity both in vitro and in vivo, with the latter mimicking the effects of exercise training on whole body metabolism. Thus, we show here that 2-HB production by skeletal muscle represents a novel mechanism for the modification of metabolism by exercise.

physiology↗

bioRxiv2022

Glutarate regulates T cell function and metabolism

T cell function is influenced by several metabolites; some acting through enzymatic inhibition of -KG-dependent dioxygenases (KGDDs), others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, with effects on T cell function and differentiation. Glutarate exerts those effects through KGDD inhibition and through direct regulation of T cell metabolism via post-translational modification of the pyruvate dehydrogenase E2 subunit. Diethyl-glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound reduces tumor growth and is correlated with increased levels of both peripheral and intratumoral cytotoxic CD8+ T cells. These results demonstrate that glutarate regulates both T cell metabolism and differentiation, with a potential role in the improvement of T cell immunotherapy.

immunology↗