Muscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia : the effects of blocking myostatin and activins
Hulmi, J., Penna, F., Pöllänen, N., Nissinen, T., Hentilä, J., Euro, L., Lautaoja, J., Ballarò, R., Soliymani, R., Baumann, M., Ritvos, O., Pirinen, E., & Lalowski, M. (2020). Muscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia : the effects of blocking myostatin and activins. Molecular Metabolism, 41, 101046. https://doi.org/10.1016/j.molmet.2020.101046
Published inMolecular Metabolism
Euro, L. |
© 2020 The Authors. Published by Elsevier GmbH
Objective Cancer cachexia and muscle loss are associated with increased morbidity and mortality. In preclinical animal models, blocking activin receptor (ACVR) ligands has improved survival and prevented muscle wasting in cancer cachexia without an effect on tumour growth. However, the underlying mechanisms are poorly understood. The present study aimed to identify cancer cachexia and soluble ACVR (sACVR) administration-evoked changes in muscle proteome. Methods Healthy and C26 tumour-bearing (TB) mice were treated with recombinant sACVR. The sACVR or PBS control were administered either prior to the tumour formation or by continued administration before and after tumour formation. Muscles were analysed by quantitative proteomics with further examination of mitochondria and nicotinamide adenine dinucleotide (NAD+) metabolism. To complement the first prophylactic experiment, sACVR (or PBS) was injected as a treatment following tumour cell inoculation. Results Muscle proteomics in TB cachectic mice revealed downregulated signatures for mitochondrial oxidative phosphorylation (OXPHOS) and increased acute phase response (APR). These were accompanied by muscle NAD+ deficiency, alterations in NAD+ biosynthesis including downregulation of nicotinamide riboside kinase 2 (Nrk2), and decreased muscle protein synthesis. The disturbances in NAD+ metabolism and protein synthesis were rescued upon treatment with sACVR. Across the whole proteome and APR in particular, Serpina3n represented the most upregulated protein and the strongest predictor of cachexia. However, the increase in Serpina3n expression associated with increased inflammation rather than decreased muscle mass and/or protein synthesis. Conclusions We present here an evidence implicating disturbed muscle mitochondrial OXPHOS proteome and NAD+ homeostasis in experimental cancer cachexia. Treatment of tumour-bearing mice with a blocker of activin receptor ligands restores depleted muscle NAD+ and Nrk2 as well as decreased muscle protein synthesis. These results point out putative new treatment therapies for cachexia. Our results also reveal that although acute phase protein Serpina3n may serve as a predictor of cachexia, it more likely reflects a condition of elevated inflammation. ...
Publication in research information system
MetadataShow full item record
- Liikuntatieteiden tiedekunta 
Related funder(s)Academy of Finland
Funding program(s)Academy Research Fellow, AoF
Additional information about fundingThis work was supported by the Academy of Finland (grant No. 275922 to JJH and 286359 to EP) and Cancer Society of Finland to JJH. The research leading to these results has also received funding from AIRC under IG 2018 - ID. 21963 project (FP).
Showing items with similar title or keywords.
Activin Receptor Ligand Blocking and Cancer Have Distinct Effects on Protein and Redox Homeostasis in Skeletal Muscle and Liver Hentilä, Jaakko; Nissinen, Tuuli; Korkmaz, Ayhan; Lensu, Sanna; Silvennoinen, Mika; Pasternack, Arja; Ritvos, Olli; Atalay, Mustafa; Hulmi, Juha (Frontiers Research Foundation, 2019)Muscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein ...
Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota : A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia? Pekkala, Satu; Keskitalo, Anniina; Kettunen, Emilia; Lensu, Sanna; Nykänen, Noora; Kuopio, Teijo; Ritvos, Olli; Hentilä, Jaakko; Nissinen, Tuuli A.; Hulmi, Juha J. (MDPI AG, 2019)Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. ...
Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses Nissinen, Tuuli; Hentilä, Jaakko; Penna, Fabio; Lampinen, Anita; Lautaoja, Juulia; Fachada, Vasco; Holopainen, Tanja; Ritvos, Olli; Kivelä, Riikka; Hulmi, Juha (Wiley, 2018)Background Cancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered. ...
Muscle and serum metabolomes are dysregulated in colon-26 tumor-bearing mice despite amelioration of cachexia with activin receptor type 2B ligand blockade Lautaoja, Juulia; Lalowski, Maciej; Nissinen, Tuuli; Hentilä, Jaakko; Shi, Yi; Ritvos, Olli; Cheng, Sulin; Hulmi, Juha (American Physiological Society, 2019)Cancer-associated cachexia reduces survival, which has been attenuated by blocking the activin receptor type 2B (ACVR2B) ligands in mice. The purpose of this study was to unravel the underlying physiology and novel cachexia ...
Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments Hulmi, Juha J.; Nissinen, Tuuli A.; Penna, Fabio; Bonetto, Andrea (MDPI, 2021)Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation ...