Patients with colorectal cancer frequently develop cachexia, leading to severe depletion of skeletal muscle. Metabolomics, through the analysis of metabolite profiles using nuclear magnetic resonance (NMR), shows promise in identifying biomarkers for diagnosis and treatment, providing crucial insights into tumours and metabolic changes, allowing for an enhanced understanding of the mechanisms related to the cancer-cachexia process.

In the present study, we analysed the most impacted metabolic pathways affected after a glycaemic clamp in the serum of patients with rectal cancer diagnosed with sarcopenia (S) or not (NS).

In this preliminary study, serum samples collected from rectal cancer patients were prepared through filtration to remove proteins and lipids, followed by the addition of deuterium buffer for magnetic field calibration. The spectra were obtained using NMR (500 MHz), allowing precise identification and quantification of metabolites in biological samples. The obtained spectra were processed by CHENOMX software for phase adjustment, baseline correction, and spectral alignment, and then analysed for metabolic pathways using MetaboAnalyst software. Finally, metabolic profiles were correlated with clinical data from patients ((S) or (NS)) and the time course of the glycaemic clamp (initial time (T0) and final time (after 120 minutes, T1)). Institutional Review Board approval (CAAE: 91217418.2.0000.5404).

A total of 7 patients were analysed, 3 S and 4 NS. All S were female, and NS group had 3 males and 1 female. The median age was 64 (43-66) years for S and 69 (58-74) years for the NS group. The M-value-TBW and M-value-FFM median (P25-P75) were 4,2 (3,40-5,55) and 4,4 (3,75-5,25), for the S group, and 7,20 (5,65-8,95) and 6,10 (5,63-6,63) for the NS group, respectively. Sarcopenic patients – S –, compared to NS patients, at T0, exhibited increased levels of glycerol (indicating mobilisation of body fat), glycine and threonine (suggesting lean body mass depletion), as well as methylhistidine (corresponding to skeletal muscle degradation), with maintained levels of alanine and urea. After 120 minutes (T1), S patients showed an increase in serum alanine, glycine, and urea, still with a high serum concentration of glycerol, though similar to NS patients, and a reduction in threonine and methylhistidine levels compared to NS patients. These metabolite alterations directly impacted metabolic pathway vias related to lipoic acid metabolism, glutathione metabolism, tryptophan metabolism, branched-chain amino acid degradation (leucine, isoleucine, and valine), glycolytic and gluconeogenic pathways, and pyruvate and pyrimidine metabolism in S patients compared to NS patients.

The study reveals that S patients present a distinct metabolic profile, impacting metabolic pathways, mainly related to cachexia syndrome effects, compared to NS individuals, thereby enhancing our understanding of the metabolic disturbances in this condition. Mendes, MCS and Madeira, BSM are sharing the first authorship. Gomes-Marcondes, MCC and Carvalheira, JBC were co-advisors in these studies.