Autophagic Signaling Promotes Systems-Wide Remodeling in Skeletal Muscle Upon Oncometabolic Stress by D2-HG

Authors

Yaqi Gao
Kyoungmin Kim
Heidi Vitrac
Rebecca L Salazar
Benjamin D Gould
Daniel Soedkamp
Weston Spivia
Koen Raedschelders
An Q Dinh
Anna G Guzman
Lin Tan
Stavros Azinas
David J R Taylor
Walter Schiffer
Daniel McNavish
Helen B Burks
Roberta A Gottlieb
Philip L Lorenzi
Blake M Hanson
Jennifer E Van Eyk
Heinrich Taegtmeyer
Anja Karlstaedt

Publication Date

8-1-2024

Journal

Molecular Metabolism

Abstract

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.

METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling.

RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle.

CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.

Keywords

Animals, Mice, Muscle, Skeletal, Autophagy, Male, Signal Transduction, Glutarates, Isocitrate Dehydrogenase, Cachexia, Female, Sirtuin 1, Mice, Inbred C57BL, Oncometabolism, Autophagy, Cachexia, Systems biology

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Supplementary Materials

PMID: 38908793