A Metabolic Change towards Fermentation Drives Cancer Cachexia in Myotubes
Open Access
- 20 June 2021
- journal article
- research article
- Published by MDPI AG in Biomedicines
- Vol. 9 (6), 698
- https://doi.org/10.3390/biomedicines9060698
Abstract
Cachexia is a disorder associated with several pathologies, including cancer. In this paper, we describe how cachexia is induced in myotubes by a metabolic shift towards fermentation, and the block of this metabolic modification prevents the onset of the cachectic phenotype. Cachectic myotubes, obtained by the treatment with conditioned medium from murine colon carcinoma cells CT26, show increased glucose uptake, decreased oxygen consumption, altered mitochondria, and increased lactate production. Interestingly, the block of glycolysis by 2-deoxy-glucose or lactate dehydrogenase inhibition by oxamate prevents the induction of cachexia, thus suggesting that this metabolic change is greatly involved in cachexia activation. The treatment with 2-deoxy-glucose or oxamate induces positive effects also in mitochondria, where mitochondrial membrane potential and pyruvate dehydrogenase activity became similar to control myotubes. Moreover, in myotubes treated with interleukin-6, cachectic phenotype is associated with a fermentative metabolism, and the inhibition of lactate dehydrogenase by oxamate prevents cachectic features. The same results have been achieved by treating myotubes with conditioned media from human colon HCT116 and human pancreatic MIAPaCa-2 cancer cell lines, thus showing that what has been observed with murine-conditioned media is a wide phenomenon. These findings demonstrate that cachexia induction in myotubes is linked with a metabolic shift towards fermentation, and inhibition of lactate formation impedes cachexia and highlights lactate dehydrogenase as a possible new tool for counteracting the onset of this pathology.This publication has 46 references indexed in Scilit:
- Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexiaJournal of Cachexia, Sarcopenia and Muscle, 2013
- Cellular and molecular mechanisms of muscle atrophyDisease Models & Mechanisms, 2013
- Understanding the mechanisms and treatment options in cancer cachexiaNature Reviews Clinical Oncology, 2012
- JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexiaAmerican Journal of Physiology-Endocrinology and Metabolism, 2012
- Cancer Cachexia: Mediators, Signaling, and Metabolic PathwaysCell Metabolism, 2012
- Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjectsJournal Of Physiology-London, 2012
- Definition and classification of cancer cachexia: an international consensusThe Lancet Oncology, 2011
- A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growthProceedings of the National Academy of Sciences of the United States of America, 2008
- Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein KinaseDiabetes, 2006
- The ubiquitin-dependent proteolytic pathway in skeletal muscle: its role in pathological statesTrends in Pharmacological Sciences, 1996