Abstract
BackgroundCachexia is one of the most important causes of cancer-related death. Supplementation with branched-chain amino acids, particularly leucine, has been used to minimise loss of muscle tissue, although few studies have examined the effect of this type of nutritional supplementation on the metabolism of the tumour-bearing host. Therefore, the present study evaluated whether a leucine-rich diet affects metabolomic derangements in serum and tumour tissues in tumour-bearing Walker-256 rats (providing an experimental model of cachexia).MethodsAfter 21 days feeding Wistar female rats a leucine-rich diet, distributed in L-leucine and LW-leucine Walker-256 tumour-bearing groups, we examined the metabolomic profile of serum and tumour tissue samples and compared them with samples from tumour-bearing rats fed a normal protein diet (C – control; W – tumour-bearing groups). We utilised 1H-NMR as a means to study the serum and tumour metabolomic profile, tumour proliferation and tumour protein synthesis pathway.ResultsAmong the 58 serum metabolites examined, we found that 12 were altered in the tumour-bearing group, reflecting an increase in activity of some metabolic pathways related to energy production, which diverted many nutrients toward tumour growth. Despite displaying increased tumour cell activity (i.e., higher Ki-67 and mTOR expression), there were no differences in tumour mass associated with changes in 23 metabolites (resulting from valine, leucine and isoleucine synthesis and degradation, and from the synthesis and degradation of ketone bodies) in the leucine-tumour group. This result suggests that the majority of nutrients were used for host maintenance.ConclusionA leucine rich-diet, largely used to prevent skeletal muscle loss, did not affect Walker 256 tumour growth and led to metabolomic alterations that may partially explain the positive effects of leucine for the whole tumour-bearing host.
Highlights
Cachexia is one of the most important causes of cancer-related death
We develop a 1H NMR metabolomic profile to evaluate the therapeutic effect of a leucine-rich diet in rats bearing Walker 256 tumours, which offer an experimental model of cachexia [34]
Tumour weight and vessel number did not differ between the W and LW groups (Table 2 and Fig. 1a and e), even though the tumour tissue of the LW group showed an increase in mTOR and Ki-67 protein expression in comparison to W group (Fig. 1b, c and d)
Summary
Cachexia is one of the most important causes of cancer-related death. Supplementation with branched-chain amino acids, leucine, has been used to minimise loss of muscle tissue, few studies have examined the effect of this type of nutritional supplementation on the metabolism of the tumourbearing host. Cachexia is one of the leading causes of death in cancer patients, accounting for nearly 30 % of such cases [1,2,3], and is a complex metabolic and nutritional syndrome characterised by involuntary weight loss that is mainly due to Cancer cachexia leads to metabolic derangements, and an increasing number of studies are emerging that examine altered metabolite profiles associated with various diseases, especially for cancer-associated cachexia [6]. Shen and colleagues [8] reported potential biomarkers in the urine of Walker-256 tumour-bearing rats during cancer progression, hypothesising that this alteration might have resulted from elevated cell proliferation, a reduction in the ß-oxidation of fatty acids and poor renal tubular reabsorption. The identities, concentrations and fluxes of metabolites are the final product of interactions between gene expression, protein expression and the cellular environment [11] and can serve as indicators of the overall physiological status of patients [12]
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