Oncometabolism Drives Autophagy Activation in Skeletal Muscle

Karlstaedt, A.; Vitrac, H.; Salazar, R. L.; Gould, B. D.; Soedkamp, D.; Spivia, W.; Raedschelders, K.; Dinh, A. Q.; Guzman, A.; Tan, L.; Azinas, S.; Taylor, D. J. R.; Schiffer, W.; McNavish, D.; Burks, H. B.; Gottlieb, R. A.; Lorenzi, P. L.; Hanson, B.; Van Eyk, J. E.; Taegtmeyer, H.

doi:10.1101/2020.10.13.338202

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bioRxiv · 10.1101/2020.10.13.338202

Oncometabolism Drives Autophagy Activation in Skeletal Muscle

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Abstract

About 20-30% of cancer-associated deaths are due to complications from cachexia which is characterized by skeletal muscle atrophy. Metabolic reprogramming in cancer cells causes body-wide metabolic and proteomic remodeling, which remain poorly understood. Here, we present evidence that the oncometabolite D-2-hydroxylgutarate (D2-HG) impairs NAD+ redox homeostasis in skeletal myotubes, causing atrophy via deacetylation of LC3-II by the nuclear deacetylase Sirt1. Overexpression of p300 or silencing of Sirt1 abrogate its interaction with LC3, and subsequently reduced levels of LC3 lipidation. Using RNA-sequencing and mass spectrometry-based metabolomics and proteomics, we demonstrate that prolonged treatment with the oncometabolite D2-HG in mice promotes cachexia in vivo and increases the abundance of proteins and metabolites, which are involved in energy substrate metabolism, chromatin acetylation and autophagy regulation. We further show that D2-HG promotes a sex-dependent adaptation in skeletal muscle using network modeling and machine learning algorithms. 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.

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Karlstaedt, A., Vitrac, H., Salazar, R. L., Gould, B. D., Soedkamp, D., Spivia, W., Raedschelders, K., Dinh, A. Q., Guzman, A., Tan, L., Azinas, S., Taylor, D. J. R., Schiffer, W., McNavish, D., Burks, H. B., Gottlieb, R. A., Lorenzi, P. L., Hanson, B., Van Eyk, J. E., Taegtmeyer, H.. 2020-10-14. Oncometabolism Drives Autophagy Activation in Skeletal Muscle. https://doi.org/10.1101/2020.10.13.338202

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