A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue

Author:

Wadsworth Brennan J1ORCID,Leiwe Marina1ORCID,Minogue Eleanor A2,Cunha Pedro P2ORCID,Engman Viktor3,Brombach Carolin1,Asvestis Christos1ORCID,Sah-Teli Shiv K45,Marklund Emilia1,Karppinen Peppi4ORCID,Ruas Jorge L3ORCID,Rundqvist Helene6ORCID,Lanner Johanna T3,Johnson Randall S2ORCID

Affiliation:

1. Department of Cell and Molecular Biology, Karolinska Institute

2. Department of Physiology, Development and Neuroscience, University of Cambridge

3. Department of Physiology and Pharmacology, Karolinska Institute

4. Faculty of Medical Biochemistry and Molecular Biology, University of Oulu

5. Department of Biochemistry, University of Cambridge

6. Department of Laboratory Medicine, Karolinska Institutet

Abstract

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which 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/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.

Funder

Vetenskapsrådet

Barncancerfonden

Wellcome Trust

Canadian Institutes of Health Research

Cancerfonden

Knut och Alice Wallenbergs Stiftelse

Fundação para a Ciência e a Tecnologia

Publisher

eLife Sciences Publications, Ltd

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