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

Abstract

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.

Metabolomic Profiling of Respiratory Muscles and Lung in Response to Long-Term Controlled Mechanical Ventilation

“…We have previously reported dramatic muscle wasting of limb and trunk muscles in response to long-term CMV ( Ochala et al, 2011 ; Corpeno et al, 2014 ; Salah et al, 2016 ). In accordance with previous transcriptomic analyses, metabolite alterations were associated with an accelerated degradation of myofibrillar proteins in response to immobilization and CMV such as augmented levels of branch-chain amino acids (BCAAs; leucine, isoleucine, and valine) and their catabolic metabolites in both diaphragm and intercostals ( Figures 5A , 6 ), since myofibrillar proteins are composed of 18% BCAAs ( Baracos and Mackenzie, 2006 ; Chiocchetti et al, 2021 ). DMs involved in “Dipeptide” were significantly decreased, especially in the diaphragm ( Figures 5A , 7D ).…”

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

“…These results were similar to previous studies using the same experimental model [26][27][28]. Of note, these alterations happened in both tumour-bearing groups but were more severe in WW animals, likely suggesting a higher spoliation in younger hosts, corroborating our previous report [17]. Although we did not find differences in relative liver weight in the present study, we found an altered liver metabolomic profile, gene and protein expressions imposed by the tumour growth, which were differentially affected by life stage in tumour-bearing animals.…”

“…Our previous 1 H-NMR-based study showed serum metabolite alterations associated with muscle metabolic pathways related to energy production and protein breakdown in Walker-256 tumourbearing animals [15,16]. We also found metabolic changes in skeletal muscle, showing altered metabolites mainly related to increased levels of amino acids and altered energetic metabolism, suggesting an expressive catabolic process and energy production in the youngest host, depicting differences between muscle responses depending on the host developmental stages [17].…”

“…In this way, the tumour evolution probably affected the liver mitochondrial activity by enhancing de novo synthesis of choline and betaine as well, using phosphocholine (despite being increased only in the AW group). This new synthesis occurs even under the lower nutritional provision, as found by the anorexia presented in tumour-bearing mice [17]. Therefore, even at increased levels of choline or betaine, there was a decrease in the enzymes CII and CIII of the OXPHOS mitochondrial complex, suggesting the diminished mitochondrial activity in the liver of the WW group.…”

Metabolomics and its Applications in Cancer Cachexia

“…The metabolic alterations mostly focused in several metabolic pathways, including amino acid biosynthesis which was upregulated in the aging group and downregulated in the tumor groups (Viana et al, 2020). Recently, they also performed NMR-based metabolomic analysis on gastrocnemius derived from weanling and young adult rats, aiming to explore metabolic alterations in cachectic hosts during the whole lifespan (Chiocchetti et al, 2021). They indicated that the most significant variations of metabolites such as glutamate, glutamine, glycine, and methylhistidine, might be associated with the early muscle catabolism and declined energy generation in cachectic muscles.…”