Metabolic phenotyping to provide insight in mechanisms underlying muscle weakness and wasting in patients with cancer

Rationale: Cancer is characterized by low plasma concentrations of arginine (ARG), glutamine (GLN) and citrulline (CIT). This study investigates the relationship between glutamine-related metabolism and muscle strength in patients with advanced cancer using metabolic phenotyping.
Methods: In 16 patients with solid tumours (C) and 16 age- and gender-matched healthy controls (H), fasted plasma amino acid concentrations and whole body ARG, GLN, CIT and GLU rates of appearance (Ra) were assessed by pulse IV administration of L-[Guanidino-15N2]-Arginine, L-[5-15N]-glutamine, L-[ureido-13C-2H2]-Citrulline, L-[1,2-13C2] Glutamate and 2H3-Leucine (LEU), and clearance rates calculated. Handgrip, inspiratory and leg muscle strength and physical function (EORTC-QLQc30 questionnaire) were assessed, and amino acid concentrations and isotope enrichments by LCMS/MS. Statistics was done by unpaired t-tests and spearman correlation tests.
Results: Ra and clearance rate of GLN were higher in C than in H (Ra GLN: 491.4±32.0 vs. 325.2±51.5 μmol/kg ffm/h, p=0.008, clearance GLN 1.13±0.08 vs 0.70±0.09, p<0.001) as well as that of the GLN related amino acids ARG, CIT and LEU (p<0.05). The conversion of ARG to CIT (marker of NO synthesis), CIT to ARG (de novo ARG production) and GLU to GLN (marker of muscle GLN production) were also higher in C (P<0.01) and negatively correlated to FFMi (r<-0.5, P<0.05). Plasma BCAA was positively correlated to handgrip and inspiratory muscle strength, and physical function (R>0.4, P<0.05). RaCIT was negatively related to leg extension strength (r=-0.7, P<0.01).
Conclusion: Metabolic phenotyping using novel tracer pulse methodology showed that disturbances in glutamine related metabolism are associated with muscle wasting and weakness in patients with cancer.