Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer

TL;DR

This study finds that specific changes in metabolism are linked to weight loss, muscle loss, and poor physical function in men with cancer, offering potential targets for treatment.

Contribution

The study is the first to identify distinct metabolomic signals associated with impaired physical function in cancer cachexia.

Findings

Weight loss is linked to altered metabolism in plasma, including microbial and fatty acid pathways.

Reduced muscle mass is associated with changes in skeletal muscle metabolism, such as fatty acid and histidine pathways.

Poor physical function shows distinct metabolic patterns in plasma and muscle, separate from those of weight loss or muscle loss.

Abstract

Treatments for cancer cachexia, defined as involuntary weight and muscle mass loss leading to significant functional impairment, remain unavailable partly due to insufficient improvement of clinically meaningful outcomes in current trials. By reflecting downstream effects of cellular function, metabolomics may identify mechanisms contributing to poor functional performance. Previous metabolomic studies in cancer cachexia have identified alterations in amino acid metabolism with weight loss or low muscularity; none have examined perturbations with poor physical function. We hypothesized that distinct metabolic signals in plasma and muscle are associated with weight loss, low muscle mass, and impaired function in cancer cachexia.

We enrolled patients planning elective laparotomy for gastrointestinal or genitourinary cancer. Handgrip strength (HGS), stair climb power (SCP), and fasting plasma were collected within 2 weeks prior to surgery; rectus abdominis samples were obtained during surgery. Metabolomic perturbations associated with physical function (HGS, SCP), muscularity (lumbar cross‐sectional area ‘CSA’ from opportunistic CT), or weight loss (> 5% over previous 6 months) were examined in plasma and muscle. The Mann–Whitney U‐test compared metabolite abundance between weight‐losing and weight‐stable patients, while Spearman's correlation tested associations of abundance with CSA, HGS, or SCP. The ‘Globaltest’ method assessed pathway alterations with weight loss, CSA, HGS, or SCP; the Benjamini‐Hochberg adjustment was used to control for false discovery.

Patients (N = 72) were male, median age 65 [interquartile range: 59–70], with 57% genitourinary cancer. Plasma and skeletal muscle metabolomic data were collected (N = 64 and N = 68, respectively). Weight loss was associated with significantly altered microbial, amino acid/derivative, fatty acid/lipid, and caffeine‐related metabolism pathways in plasma (adjusted p < 0.1). Lower CSA was associated with significantly altered fatty acid/lipid, galactose, glycerophospholipid, and histidine metabolism and bile secretion pathways in skeletal muscle (adjusted p < 0.1). Worse HGS was nominally associated with altered plasma branched chain amino acid biosynthesis and altered skeletal muscle glutathione metabolism (unadjusted p ≤ 0.05), while worse SCP was nominally associated with altered skeletal muscle amino sugar/nucleotide sugar metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis (unadjusted p ≤ 0.05).

Significant metabolomic alterations in plasma and skeletal muscle characterized cancer‐related weight loss and reduced CSA, respectively. Nominal, function‐specific alterations were detected with worse HGS and SCP, which were distinct from those associated with weight loss or low CSA. Future larger studies may further characterize metabolomic profiles related to various functional outcomes and guide development of therapeutic targets to improve functional performance.

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