Kunz 2020 J Biol Chem

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Publications in the MiPMap
Kunz HE, Dorschner JM, Berent TE, Meyer T, Wang X, Jatoi A, Kumar R, Lanza IR (2020) Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting. J Biol Chem 295:17441-59.

» PMID: 33004439 Open Access

Kunz Hawley E, Dorschner Jessica M, Berent Taylor E, Meyer Thomas, Wang Xuewei, Jatoi Aminah, Kumar Rajiv, Lanza Ian R (2020) J Biol Chem

Abstract: Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected seven-week old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared to controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine, in tumor-bearing mice compared to control mice. Compared to healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia. Keywords: Cachexia, Cancer, Metabolomics, Methylarginines, Mitochondria, Protein synthesis, Skeletal muscle Bioblast editor: Plangger M O2k-Network Lab: US MN Rochester Nair KS


Labels: MiParea: Respiration  Pathology: Cancer 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Intact cells 


Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2020-11, AmR