Leucine-rich diet supplementation modulates foetal muscle protein metabolism impaired by Walker-256 tumour

Abstract

BackgroundCancer-cachexia induces a variety of metabolic disorders of protein turnover and is more pronounced when associated with pregnancy. Tumour-bearing pregnant rats have impaired protein balance, which decreases protein synthesis and increases muscle breakdown. Because branched-chain amino acids, especially leucine, stimulate protein synthesis, we investigated the effect of a leucine-rich diet on protein metabolism in the foetal gastrocnemius muscles of tumour-bearing pregnant rats.MethodsFoetuses of pregnant rats with or without Walker 256 tumours were divided into six groups. During the 20 days of the experiment, the pregnant groups were fed with either a control diet (C, control rats; W, tumour-bearing rats; Cp, rats pair-fed the same normoprotein-diet as the W group) or with a leucine-rich diet (L, leucine rats; LW, leucine tumour-bearing rats; and Lp, rats pair-fed the same leucine-rich diet as the LW group). After the mothers were sacrificed, the foetal gastrocnemius muscle samples were resected, and the protein synthesis and degradation and tissue chymotrypsin-like, cathepsin and calpain enzyme activities were assayed. The muscle oxidative enzymes (catalase, glutathione-S-transferase and superoxide dismutase), alkaline phosphatase enzyme activities and lipid peroxidation (malondialdehyde) were also measured.ResultsTumour growth led to a reduction in foetal weight associated with decreased serum protein, albumin and glucose levels and low haematocrit in the foetuses of the W group, whereas in the LW foetuses, these changes were less pronounced. Muscle protein synthesis (measured by L-[3H]-phenylalanine incorporation) was reduced in the W foetuses but was restored in the LW group. Protein breakdown (as assessed by tyrosine release) was enhanced in the L and W groups, but chymotrypsin-like activity increased only in group W and tended toward an increase in the LW foetuses. The activity of cathepsin H was significantly higher in the W group foetuses, but the proteolytic calcium-dependent pathway showed similar enzyme activity. In parallel, an intense oxidative stress process was observed only in the group W foetuses.ConclusionsThese data suggested that the proteasomal and lysosomal proteolytic pathways and oxidative stress are likely to participate in the process of foetal muscle catabolism of Walker’s tumour-bearing pregnant rats. The present work shows that foetal muscle can be protected by supplementation with a leucine-rich diet.

A Leucine-Rich Diet Modulates the Tumor-Induced Down-Regulation of the MAPK/ERK and PI3K/Akt/mTOR Signaling Pathways and Maintains the Expression of the Ubiquitin-Proteasome Pathway in the Placental Tissue of NMRI Mice1

“…Therefore, we found evidence of the benefits produced by leucine-rich dietary supplementation, not only in the placental tissue but also in the fetus: fetal weight was higher in the LMAC group and fetal resorption was lower in the LMAC compared to the MAC group, in agreement with our previous data [19,33]. According to these data, the placenta cell-signaling pathway was unchanged by the leucine-rich diet even in the LMAC group compared to the C and L groups.…”

“…As observed in our previous reports and in those from other researchers, the ubiquitinproteasome pathway in skeletal muscle is activated during cancer evolution, decreasing the protein content in response to the elevated release of tyrosine relative to the increased expression of 20S and other proteasomal subunits, ultimately leading to protein degradation [19,23,50,53,54]. Likewise, in response to tumor growth, the placental tissues had a higher protein expression of the 20S and 19S subunits, in line with an increase of protein catabolism.…”

“…Certain stress situations such as protein restriction and some diseases, including cancer, can jeopardize the function of the placenta and often lead to intrauterine growth restriction (IUGR), as shown by our previous findings [17][18][19]. The activity of placental amino acid transporters is decreased in IUGR.…”

Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

“…Our previous work showed some important impairments in skeletal muscle in tumour‐bearing rats, which had increased chymotrypsin activity, representing enhancements of the ubiquitin–proteasome pathway . The present results likely suggest that the higher proteolytic activity (increased chymotrypsin activity) that is associated with higher cell activity (higher AP activity) in heart tissue could be responsible for the ECG failure that was observed only in group W. In our previous research, as also found here, the leucine‐rich diet also minimized the observed changes in those enzymes, even in the heart.…”

Leucine‐rich diet minimises liver glycogen mobilisation and modulates liver gluconeogenesis enzyme expression in tumour‐bearing cachectic rats

“…One of these strategies is nutritional supplementation with leucine, which is a branched‐chain amino acid (BCAA) that plays an important role in skeletal muscle metabolism [16]. Leucine efficiently improves skeletal muscle protein synthesis in patients [17, 18] and in animals, as shown previously [19–22]. Leucine alone and in a complete BCAA mixture stimulates protein synthesis and decreases protein proteolysis [23–25].…”