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

Sarcopenia among the older population has been growing over the last few years. In addition, the incidence of cancers increases with age and, consequently, the development of cachexia related cancer. Therefore, the elucidation of the metabolic derangements of sarcopenia and cachexia are important to improve the survival and life quality of cancer patients. We performed the 1H-NMR based serum metabolomics in adult (A) and ageing (S) Walker 256 tumour-bearing rats in different stages of tumour evolution, namely intermediated (Wi) and advanced (Wa). Among 52 serum metabolites that were identified, 21 were significantly increased in S and 14 and 19 decreased in the Wi and Wa groups, respectively. The most impacted pathways by this metabolic alteration were related by amino acid biosynthesis and metabolism, with an upregulation in S group and downregulation in Wi and Wa groups. Taken together, our results suggest that the increase in metabolic profile in ageing rats is associated with the higher muscle protein degradation that releases several metabolites, especially amino acids into the serum. On the other hand, we hypothesise that the majority of metabolites released by muscle catabolism are used by tumours to sustain rapid cell proliferation and tumorigenesis.

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Leucine-Rich Diet Improved Muscle Function in Cachectic Walker 256 Tumour-Bearing Wistar Rats

Cells ◽

10.3390/cells10123272 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3272

Author(s):

Laís Rosa Viana ◽

Gabriela de Matuoka e Chiocchetti ◽

Lucas Oroy ◽

Willians Fernando Vieira ◽

Estela Natacha Brandt Busanello ◽

...

Keyword(s):

Protein Degradation ◽

Muscle Atrophy ◽

Muscle Function ◽

Cancer Cachexia ◽

Muscle Protein ◽

Tumour Bearing ◽

Walker 256 Tumour ◽

Muscle Protein Degradation ◽

Walker 256

Skeletal muscle atrophy occurs in several pathological conditions, such as cancer, especially during cancer-induced cachexia. This condition is associated with increased morbidity and poor treatment response, decreased quality of life, and increased mortality in cancer patients. A leucine-rich diet could be used as a coadjutant therapy to prevent muscle atrophy in patients suffering from cancer cachexia. Besides muscle atrophy, muscle function loss is even more important to patient quality of life. Therefore, this study aimed to investigate the potential beneficial effects of leucine supplementation on whole-body functional/movement properties, as well as some markers of muscle breakdown and inflammatory status. Adult Wistar rats were randomly distributed into four experimental groups. Two groups were fed with a control diet (18% protein): Control (C) and Walker 256 tumour-bearing (W), and two other groups were fed with a leucine-rich diet (18% protein + 3% leucine): Leucine Control (L) and Leucine Walker 256 tumour-bearing (LW). A functional analysis (walking, behaviour, and strength tests) was performed before and after tumour inoculation. Cachexia parameters such as body weight loss, muscle and fat mass, pro-inflammatory cytokine profile, and molecular and morphological aspects of skeletal muscle were also determined. As expected, Walker 256 tumour growth led to muscle function decline, cachexia manifestation symptoms, muscle fibre cross-section area reduction, and classical muscle protein degradation pathway activation, with upregulation of FoxO1, MuRF-1, and 20S proteins. On the other hand, despite having no effect on the walking test, inflammation status or muscle oxidative capacity, the leucine-rich diet improved muscle strength and behaviour performance, maintained body weight, fat and muscle mass and decreased some protein degradation markers in Walker 256 tumour-bearing rats. Indeed, a leucine-rich diet alone could not completely revert cachexia but could potentially diminish muscle protein degradation, leading to better muscle functional performance in cancer cachexia.

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Leucine-rich Diet Improved Muscle Function in Cachectic Walker 256 Tumor-bearing Wistar Rats

10.21203/rs.3.rs-550186/v1 ◽

2021 ◽

Author(s):

Laís Viana ◽

Gabriela Chiocchetti ◽

Lucas Oroy ◽

Willians Vieira ◽

Carla Salgado ◽

...

Keyword(s):

Protein Degradation ◽

Muscle Atrophy ◽

Muscle Function ◽

Cancer Cachexia ◽

Muscle Protein ◽

Tumor Bearing ◽

Muscle Protein Degradation ◽

Walker 256 ◽

Walker 256 Tumor

Abstract Background: Skeletal muscle atrophy occurs in several pathological conditions such as cancer, a condition termed cancer cachexia. This condition is associated with an increase in morbidity and poor treatment response, decreasing quality of life, and increased mortality in cancer patients. A leucine-rich diet could be used as a coadjutant therapy preventing muscle atrophy in cancer cachexia hosts. Besides muscle atrophy, muscle function loss is even more important to the patient’s quality of life. Therefore, this study aimed to evaluate the effects of leucine-rich diet on muscle function activity of cachectic Walker 256 tumor-bearing rats and to correlate such effects with molecular pathways of muscle atrophy. Methods: Adult Wistar rats were randomly distributed into four experimental groups. Two groups were fed with a control diet: Control (C) and Walker 256 tumor-bearing (W), and two other groups were fed with a leucine-rich diet: Leucine Control (L) and Leucine Walker 256 tumor-bearing (LW). The functional analysis (walking, behavior, and strength tests) was measured and before and after tumor inoculation. Cachexia parameters such as body weight loss, muscle and fat mass, pro-inflammatory cytokine profile, and molecular and morphological aspects of skeletal muscle were also performed. Results: Walker 256 tumor growth led to muscle function decline, cachexia manifestation symptoms, muscle fiber cross-section area reduction, associated with the altered morphological pattern and classical muscle protein degradation pathway activation, with up-regulation of FoXO1, MuRF1, and 20S proteins. On the other hand, a leucine-rich diet improved muscle strength while reducing the decline of walking and behavior, partially improving the cachexia manifestations and preventing muscle atrophy and protein degradation in Walker 256 tumor-bearing rats. Conclusions: A leucine-rich diet diminished muscle protein degradation and enhanced oxidative pathways, leading to better muscle functional performance.

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

Metabolites ◽

10.3390/metabo11060404 ◽

2021 ◽

Vol 11 (6) ◽

pp. 404

Author(s):

Gabriela de Matuoka e Chiocchetti ◽

Leisa Lopes-Aguiar ◽

Natália Angelo da Silva Miyaguti ◽

Lais Rosa Viana ◽

Carla de Moraes Salgado ◽

...

Keyword(s):

Skeletal Muscle ◽

Time Course ◽

Cancer Cachexia ◽

Tumour Bearing ◽

Walker 256 Tumour ◽

Walker 256 ◽

Muscle Changes ◽

The Right ◽

Biomarker Research ◽

Host Metabolism

Cancer cachexia is a severe wasting condition that needs further study to find ways to minimise the effects of damage and poor prognosis. Skeletal muscle is the most impacted tissue in cancer cachexia; thus, elucidation of its metabolic alterations could provide a direct clue for biomarker research and be applied to detect this syndrome earlier. In addition, concerning the significant changes in the host metabolism across life, this study aimed to compare the metabolic muscle changes in cachectic tumour-bearing hosts at different ages. We performed 1H-NMR metabolomics in the gastrocnemius muscle in weanling and young adult Walker-256 tumour-bearing rats at different stages of tumour evolution (initial, intermediate, and advanced). Among the 49 metabolites identified, 24 were significantly affected throughout tumour evolution and 21 were significantly affected regarding animal age. The altered metabolites were mainly related to increased amino acid levels and changed energetic metabolism in the skeletal muscle, suggesting an expressive catabolic process and diverted energy production, especially in advanced tumour stages in both groups. Moreover, these changes were more severe in weanling hosts throughout tumour evolution, suggesting the distinct impact of cancer cachexia regarding the host’s age, highlighting the need to adopting the right animal age when studying cancer cachexia.

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Leucine-Rich Diet and Light Aerobic Training Modulate GLUT4 Expression And Increase the Glycogen Content in the Gastrocnemius Muscle of Walker-256 Tumour-Bearing Rats

Journal of Physiobiochemical Metabolism ◽

10.4172/2324-8793.1000112 ◽

2014 ◽

Vol 03 (01) ◽

Author(s):

Aline T Toneto

Keyword(s):

Gastrocnemius Muscle ◽

Glycogen Content ◽

Aerobic Training ◽

Tumour Bearing ◽

Glut4 Expression ◽

Walker 256 Tumour ◽

Walker 256

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Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats

Metabolites ◽

10.3390/metabo11120831 ◽

2021 ◽

Vol 11 (12) ◽

pp. 831

Author(s):

Natália Angelo da Silva Miyaguti ◽

Gabriela de Matuoka e Chiocchetti ◽

Carla de Moraes Salgado ◽

Leisa Lopes-Aguiar ◽

Lais Rosa Viana ◽

...

Keyword(s):

Young Adult ◽

Cancer Cachexia ◽

Liver Lipid ◽

Preclinical Model ◽

Energy Status ◽

Advanced Cancer Patients ◽

Adult Rats ◽

Tumour Bearing ◽

Walker 256 Tumour ◽

Walker 256

Cancer cachexia occurs in up to 85% of advanced cancer patients, affecting different tissues and organs, mainly the liver, which plays a central role in body metabolism control. However, liver responses to cancer cachexia progression are still poorly understood. Considering the possible different challenges provided by the rodent’s phase of life and the cachexia progression, we evaluated the liver metabolic alterations affected by Walker-256 tumour growth in weanling and young-adult rats. For this, we applied a metabolomics approach associated with protein and gene expression analyses. Higher amino acid levels and impaired glucose metabolism were important features in tumour-bearing animals’ liver tissue. The weanling hosts had more pronounced cachexia, with higher carcass spoliation, liver lipid metabolism and impaired CII and CIV mitochondrial complexes. The liver alterations in young adult tumour-bearing rats were related to energy status and nucleotide metabolites, such as uridine, NAD+, xanthosine, hypoxanthine and inosine. In conclusion, the Walker-256 tumour-induced cachexia impaired liver metabolism, being more severe in the weanling hosts. Further studies are needed to correlate these changes in the preclinical model, which can be correlated to the clinical features of cancer cachexia, allowing for a translational potential involving the liver function and its responses to potential treatments.

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(1)H-NMRI metabolomic profile of skeletal muscle was altered by maternal nutritional supplementation with leucine in adult offspring tumour-bearing rats

Revista dos Trabalhos de Iniciação Científica da UNICAMP ◽

10.20396/revpibic262018203 ◽

2018 ◽

Author(s):

Beatriz Schincariol Manhe ◽

Maria Cristina Cintra Gomes Marcondes ◽

Gabriela Sales dos Santos ◽

Sarah Christine Pereira de Oliveira ◽

Natália Miyaguti Angelo da Silva

Keyword(s):

Skeletal Muscle ◽

Life Quality ◽

Nutritional Supplementation ◽

Adult Offspring ◽

Leucine Supplementation ◽

Tumour Bearing ◽

Epigenetic Effect ◽

Walker 256 Tumour ◽

Regulatory Effects ◽

Branched Chain

Cachexia is a cancer-associated metabolic syndrome that causes muscle spoliation, which leads to a reduced life quality of cancer patients. Maternal nutritional supplementation with the branched-chain amino acid leucine has been studied as an attempt to minimise/prevent the muscle waste, as an epigenetic effect from pregnancy and weaning periods during the environment modulatory role. Metabolomic analysis is an important technique to evaluate the preventive effects of maternal nutritional supplementation in a cachexia process. Thus, the present study analysed the possible regulatory effects of this supplementation on muscle metabolic profile of the adult offspring rats bearing a Walker-256 tumour. The skeletal muscle (gastrocnemius) was processed by 1H-NMRI analysis to determine the metabolomic profiles. The tumour-bearing rats were spoiled and had an increased muscle energy expenditure. The maternal leucine supplementation improved the energy availability for muscle function and activity.

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