L-leucine dietary supplementation modulates muscle protein degradation and increases pro-inflammatory cytokines in tumour-bearing rats

Abstract

Cancer cachexia is characterised by involuntary weight loss associated with systemic inflammation and metabolic changes. Studies aimed at maintaining lean body mass in cachectic tumour-bearing hosts have made important contributions reducing the number of deaths and improving the quality of life. In recent years, leucine has demonstrated effective action in maintaining lean body mass by decreasing muscle protein degradation. Currently, there is a growing need to understand how leucine stimulates protein synthesis and acts protectively in a cachectic organism. Thus, this study aimed to assess the effects of a leucine-rich diet on protein degradation signalling in muscle over the course of tumour growth. Animals were distributed into four experimental groups, which did or did not receive 2×10 viable Walker-tumour cells. Some were fed a leucine-rich diet, and the groups were subsequently sacrificed at three different time points of tumour evolution (7th, 14th, and 21st days). Protein degradation signals, as indicated by ubiquitin-proteasome subunits (11S, 19S, and 20S) and pro- and anti-inflammatory cytokines, were analysed in all experimental groups. In tumour-bearing animals without nutritional supplementation (W7, W14, and W21 groups), we observed that the tumour growth promoted a concurrent decrease in muscle protein, a sharp increase in pro-inflammatory cytokines (TNFα, IL-6, and IFNγ), and a progressive increase in proteasome subunits (19S and 20S). Thus, the leucine-supplemented tumour-bearing groups showed improvements in muscle mass and protein content, and in this specific situation, the leucine-rich diet led to an increase on the day in cytokine profile and proteasome subunits mainly on the 14th day, which subsequently had a modulating effect on tumour growth on the 21st day. These results indicate that the presence of leucine in the diet may modulate important aspects of the proteasomal pathway in cancer cachexia and may prevent muscle wasting due to the decrease in the cachexia index.

Leucine Improved Growth Performance, Muscle Growth, and Muscle Protein Deposition Through AKT/TOR and AKT/FOXO3a Signaling Pathways in Hybrid Catfish Pelteobagrus vachelli × Leiocassis longirostris

“…Muscle atrophy F-box (MAFBX) and muscle Ring finger 1 (MURF-1) are responsible for increased protein degradation through the UPP pathway, which can actually be considered the master genes for muscle atrophy and wasting [39,45,46]. Leu could increase muscle protein deposition by regulating protein synthesis and protein degradation in mammals [29,47]. Dietary optimal Leu up-regulated liver TOR mRNA expression in juvenile hybrid grouper and juvenile blunt snout bream [20,21].…”

Leucine and Its Importance for Cell Signalling Pathways in Cancer Cachexia-Induced Muscle Wasting

“…Some evidence suggests that leucine uses the insulin signalling pathway, but the exact mechanism of triggering the mTOR complex remains under debate [25]. Nutritional supplementation with leucine stimulated the incorporation of phenylalanine in muscle in an experimental cachexia model, confirming an increased protein synthesis and also an increasing muscle mass [26,27]. Subunits of the mTORC1 complex (i.e., Raptor and GβL) and substrates belonging to the downstream pathway (i.e., 4E-BPs, eIF4A, eIF4B, eIF4E, including S6K1), which represent the key points within the metabolism of proteins through mTOR, are highly increased in the muscle of Walker-256 tumour-bearing animals subjected to leucine nutritional supplementation [27][28][29].…”

“…Proteasome degradation results in 7-9 amino acid peptides, which are subsequently degraded by cytosolic proteases. During muscle wasting, the activity of chymotrypsin is increased, as is the expression of 19S, 11S, and 20S, all of which are modulated by the nutritional supplementation of leucine [27,65,66].…”

1H-NMR Based Serum Metabolomics Identifies Different Profile between Sarcopenia and Cancer Cachexia in Ageing Walker 256 Tumour-Bearing Rats

“…Our previous studies have shown that the Walker 256 tumour growth-an experimental model of cachexia-led to metabolomic [13] and metabolic [14] alterations, and increased the muscle proteasomal activity [15,16] in adult rats. However, to the best of our knowledge, the biomarkers-related to sarcopenia and cachexia in senile cancer animals are not yet totally known.…”