Leucine-Rich Diet Modulates the Metabolomic and Proteomic Profile of Skeletal Muscle during Cancer Cachexia

Abstract

Background: Cancer-cachexia induces a variety of metabolic disorders, including skeletal muscle imbalance. Alternative therapy, as nutritional supplementation with leucine, shows a modulatory effect over tumour damage in vivo and in vitro. Method: Adult rats distributed into Control (C), Walker tumour-bearing (W), control fed a leucine-rich diet (L), and tumour-bearing fed a leucine-rich diet (WL) groups had the gastrocnemius muscle metabolomic and proteomic assays performed in parallel to in vitro assays. Results: W group presented an affected muscle metabolomic and proteomic profile mainly related to energy generation and carbohydrates catabolic processes, but leucine-supplemented group (WL) recovered the energy production. In vitro assay showed that cell proliferation, mitochondria number and oxygen consumption were higher under leucine effect than the tumour influence. Muscle proteomics results showed that the main affected cell component was mitochondria, leading to an impacted energy generation, including impairment in proteins of the tricarboxylic cycle and carbohydrates catabolic processes, which were modulated and improved by leucine treatment. Conclusion: In summary, we showed a beneficial effect of leucine upon mitochondria, providing information about the muscle glycolytic pathways used by this amino acid, where it can be associated with the preservation of morphometric parameters and consequent protection against the effects of cachexia.

A Time-Course Comparison of Skeletal Muscle Metabolomic Alterations in Walker-256 Tumour-Bearing Rats at Different Stages of Life

“…In addition, glycine levels, which differed with the age of the animals, could be related to the synthesis of creatine (as seen here, an increased content in parallel with tumour evolution), porphyrins, and glutathione They are also involved in the aminoacyl-tRNA biosynthesis and nitrogen metabolism pathways, likely confirming protein spoliation in the muscle mass, especially in weanling animals, and especially because of the changed amino acid profiles in both tumour-bearing animals, due to the tumour’s growth needs and also the harmful effects of tumour evolution [ 53 , 54 ]. These data corroborate the trend of π-methylhistidine increase, which corresponds directly to myosin and actin degradation in skeletal muscle, already indicated as a cachexia biomarker [ 15 , 45 , 46 , 47 ]. In parallel, these two amino acids were related to the upregulation of glyoxylate and dicarboxylate metabolism, where the reduction in glycine was in association with the increase in creatine, suggesting an intense catabolism process, especially in weanling hosts.…”

“…However, in the young adult group, π-methylhistidine increased only in the AWi (threefold change, as a trend), likely showing the onset of muscle proteolysis. Despite the decreasing muscle π-methylhistidine content in the AWm and AWa groups, some previous studies showed an increased serum content of this amino acid derivative during the intense catabolic process, as previously reported [ 45 , 46 , 47 ]. Therefore, the specific difference in metabolism in weanlings compared with young adult animals could be the result of the discrepancy in the content of this amino acid [ 48 , 49 ].…”

“…Considering the energetic metabolism in cachectic muscle tissue, the provision of ATP for muscle contraction and activity can be completely altered, diverting this energy to the protein catabolic process, since anabolic capacity in this state is jeopardised [ 4 ]. Therefore, the energy requirements of skeletal muscle can be increased, which demands an enhanced flux of glycolysis, TCA cycling, and oxidative phosphorylation, which are jeopardised due to tumour effects [ 4 , 45 , 56 , 57 ]. In this way, the TCA cycle uses other intermediate metabolites such as amino acids and fatty acids [ 58 ], which resulted here in some metabolites interfering with the whole process.…”

Present Status, Limitations and Future Directions of Treatment Strategies Using Fucoidan-Based Therapies in Bladder Cancer

“…Skeletal muscle atrophy leads to a decrease in QoL owing to a reduction in social activity and exercise, along with clinical problems including poor tolerance to cancer therapy [ 85 ]. Therefore, many investigators have focused on the prevention of chemotherapy-induced anorexia, including skeletal muscle atrophy, via various nutritional supplements or medications [ 86 , 87 , 88 ]. In the case of BC, several investigators have opined that sarcopenia, which is defined as the degenerative and systemic loss of skeletal muscle mass, plays an important role in the prognosis and survival of patients treated with radical cystectomy, systematic chemotherapy, and radiotherapy [ 89 , 90 , 91 ].…”

Addendum: Cruz, B., et al. Leucine-Rich Diet Modulates the Metabolomic and Proteomic Profile of Skeletal Muscle during Cancer Cachexia. Cancers 2020, 12, 1880

“…The authors wish to add the following statement in the Acknowledgements section of this paper [ 1 ]:…”