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

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-?B) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-?B inhibitor that targets the I?B 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?ConclusionsThe 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.

SUBMITTER: Der-Torossian H 

PROVIDER: S-EPMC3684703 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature