Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia
Open Access
- 24 January 2013
- journal article
- Published by Wiley in Journal of Cachexia, Sarcopenia and Muscle
- Vol. 4 (2), 145-155
- https://doi.org/10.1007/s13539-012-0101-7
Abstract
Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF-κB) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-κB inhibitor that targets the IκB kinase complex, to provide clinical benefit in cancer-induced skeletal muscle and cardiac atrophy. Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses. Of the 234 metabolites in the gastrocnemius, cachexia-induced changes in gastrocnemius metabolism reset the steady-state abundances of 42 metabolites (p < 0.05). These changes, not evenly distributed across biochemical categories, are concentrated in amino acids, peptides, carbohydrates and energetics intermediates, and lipids. The gastrocnemius glycolytic pathway is markedly altered—changes consistent with tumor Warburg physiology. This is the first account of a Warburg effect that is not exclusively restricted to cancer cells or rapidly proliferating nonmalignant cells. Cachectic gastrocnemius also displays tricarboxylic acid cycle disruptions, signs of oxidative stress, and impaired redox homeostasis. Compound A only partially rescues the phenotype of the cachectic gastrocnemius, failing to restore the gastrocnemius’ baseline metabolic profile. The findings in the present manuscript enumerate the metabolic consequences of cachexia in the gastrocnemius and demonstrate that NF-kB targeted treatment only partly rescues the cachectic metabolic phenotype. These data strengthen the previous findings from metabolomic characterization of serum in cachectic animals, suggesting that many of the metabolic alterations observed in the blood originate in the diseased muscle. These findings provide significant insight into the complex pathophysiology of cancer cachexia and provide objective criteria for evaluating future therapeutics. The online version of this article (doi:10.1007/s13539-012-0101-7) contains supplementary material, which is available to authorized users.This publication has 46 references indexed in Scilit:
- The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in miceNature Communications, 2012
- Oral Resveratrol Therapy Inhibits Cancer-Induced Skeletal Muscle and Cardiac Atrophy In VivoNutrition and Cancer, 2011
- NF-κB Inhibition Protects against Tumor-Induced Cardiac Atrophy in VivoThe American Journal of Pathology, 2011
- The muscle fiber type–fiber size paradox: hypertrophy or oxidative metabolism?European Journal of Applied Physiology, 2010
- Metabolomic profiling can predict which humans will develop liver dysfunction when deprived of dietary cholineThe FASEB Journal, 2010
- Expression of NF-κB and IκB proteins in skeletal muscle of gastric cancer patientsEuropean Journal of Cancer, 2010
- Understanding the Warburg Effect: The Metabolic Requirements of Cell ProliferationScience, 2009
- The IκB kinases IKKα and IKKβ are necessary and sufficient for skeletal muscle atrophyThe FASEB Journal, 2008
- Cancer Cell Metabolism: Warburg and BeyondCell, 2008
- Cachexia in cancer patientsNature Reviews Cancer, 2002