Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia

Hirak Der-Torossian, Ashley Wysong, Scott Shadfar, Monte Willis, Jonathan McDunn, Marion E. Couch

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: 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. Methods: Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)145-155
Number of pages11
JournalJournal of Cachexia, Sarcopenia and Muscle
Volume4
Issue number2
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Cachexia
NF-kappa B
Metabolomics
Neoplasms
Skeletal Muscle
Muscle Neoplasms
Wasting Syndrome
Phenotype
Therapeutics
Citric Acid Cycle
Muscular Atrophy
Metabolome
Manuscripts
Oxidation-Reduction
Oxidative Stress
Homeostasis
Transcription Factors
Phosphotransferases
Carbohydrates
Inflammation

Keywords

  • Cachexia
  • Cancer
  • Gastrocnemius
  • Metabolomics
  • Oxidative stress
  • Skeletal muscle
  • Warburg effect

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physiology (medical)

Cite this

Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia. / Der-Torossian, Hirak; Wysong, Ashley; Shadfar, Scott; Willis, Monte; McDunn, Jonathan; Couch, Marion E.

In: Journal of Cachexia, Sarcopenia and Muscle, Vol. 4, No. 2, 01.01.2013, p. 145-155.

Research output: Contribution to journalArticle

Der-Torossian, Hirak ; Wysong, Ashley ; Shadfar, Scott ; Willis, Monte ; McDunn, Jonathan ; Couch, Marion E. / Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia. In: Journal of Cachexia, Sarcopenia and Muscle. 2013 ; Vol. 4, No. 2. pp. 145-155.
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AU - McDunn, Jonathan

AU - Couch, Marion E.

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AB - Background: 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. Methods: Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses. Results: 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. Conclusions: 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.

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