Abstract
BackgroundThe exact signalling mechanism of the mTOR complex remains a subject of constant debate, even with some evidence that amino acids participate in the same pathway as used for insulin signalling during protein synthesis. Therefore, this work conducted further study of the actions of amino acids, especially leucine, in vivo, in an experimental model of cachexia. We analysed the effects of a leucine-rich diet on the signalling pathway of protein synthesis in muscle during a tumour growth time-course.MethodsWistar rats were distributed into groups based on Walker-256 tumour implant and subjected to a leucine-rich diet and euthanised at three different time points following tumour development (the 7th, 14th and 21st day). We assessed the mTOR pathway key-proteins in gastrocnemius muscle, such as RAG-A-GTPase, ERK/MAP4K3, PKB/Akt, mTOR, p70S6K1, Jnk, IRS-1, STAT3, and STAT6 comparing among the experimental groups. Serum WF (proteolysis-induced factor like from Walker-256 tumour) and muscle protein synthesis and degradation were assessed.ResultsThe tumour-bearing group had increased serum WF content, and the skeletal-muscle showed a reduction in IRS-1 and RAG activation, increased PKB/Akt and Erk/MAP4K3 on the 21st day, and maintenance of p70S6K1, associated with increases in muscle STAT-3 and STAT-6 levels in these tumour-bearing rats.ConclusionMeanwhile, the leucine-rich diet modulated key steps of the mTOR pathway by triggering the increased activation of RAG and mTOR and maintaining JNK, STAT-3 and STAT-6 levels in muscle, leading to an increased muscle protein synthesis, reducing the degradation during tumour evolution in a host, minimising the cancer-induced damages in the cachectic state.
Highlights
The exact signalling mechanism of the mechanistic target of rapamycin (mTOR) complex remains a subject of constant debate, even with some evidence that amino acids participate in the same pathway as used for insulin signalling during protein synthesis
Some evidence suggests that amino acids use the same pathway as that used for insulin signalling, the exact mechanism by which signalling in the mTOR complex occurs remains a subject of constant debate [13]
Our results showed the consequences of tumour evolution in muscle protein signalling during a time-course of Walker-256 tumour growth, and as present here, we showed that leucine participated in signalling pathways in parallel to insulin stimulation, modulating the Akt-PKB pathway, and mTOR via RAG GTPases
Summary
The exact signalling mechanism of the mTOR complex remains a subject of constant debate, even with some evidence that amino acids participate in the same pathway as used for insulin signalling during protein synthesis. MTOR acts as a sort of strategic centre from which various cellular processes are regulated [11, 12] This protein kinase is composed of the following two independently adjustable complexes: mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2), where only mTORC1 is involved in cell signalling stimulated by nutrition, as focused here mainly in muscle cells, especially because further studies about this pathway in the cachectic host are necessary. Considerable evidence regarding the mechanism by which amino acids act on mTOR pathway has been acquired from in vitro studies using cell culture techniques This information indicates the need for further studies on the action of amino acids in vivo, the primary purpose of our research. The primary purposes of our research include investigating the time-course of tumour growth under a leucine-rich diet and the effects of this diet on the activation of upstream and down-stream proteins involved in protein synthesis in the gastrocnemius muscle of Walker-tumour-bearing rats
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