# Liver–muscle metabolic crosstalk: xanthosine as a key effector of broiler myogenesis

## TL;DR

This study identifies xanthosine, a liver-produced compound, as a key driver of muscle growth in chickens, revealing a new metabolic link between the liver and muscles.

## Contribution

The study discovers xanthosine as a novel effector linking liver caffeine metabolism to enhanced muscle growth in broilers.

## Key findings

- Xanthosine, derived from hepatic caffeine metabolism, promotes myoblast proliferation and skeletal muscle growth in broilers.
- High-body-weight broilers show elevated plasma xanthosine levels and activated caffeine metabolism pathways.
- In ovo xanthosine administration increases post-hatch growth performance and muscle mass.

## Abstract

Nutritional strategies aimed at augmenting growth performance remain a central focus in poultry science. The liver, as a pivotal metabolic organ, exerts profound influence on skeletal muscle development. Nevertheless, the mechanistic interplay between hepatic metabolism and myogenesis has not been fully delineated. Here, by integrating multi-omics analyses with functional validation, we identified xanthosine, a metabolic derivative of hepatic caffeine catabolism, as a previously unrecognized regulator of broiler muscle growth. We further elucidated its mechanistic role in promoting myoblast proliferation.

Comparative phenotypic assessment of high- and low-body-weight broilers revealed substantial differences in breast muscle mass. Metagenomic profiling of cecal microbiota demonstrated only a limited association between microbial composition and body weight. In contrast, untargeted plasma metabolomics uncovered a systemic upregulation of amino acid metabolism in high-body-weight broilers, concomitant with a pronounced activation of caffeine metabolism. Consistently, hepatic transcriptomic profiling revealed marked induction of cytochrome P450 family 1 subfamily A member 2 (CYP1A2), encoding a key enzyme catalyzing caffeine catabolism. Integrated KEGG pathway enrichment across metabolomic and transcriptomic datasets highlighted caffeine metabolism as a significantly perturbed pathway. Among its downstream metabolites, plasma xanthosine was robustly elevated in high-body-weight broilers. Functional validation via in ovo injection demonstrated that xanthosine administration significantly augmented post-hatch growth performance by increasing skeletal muscle mass. Mechanistic investigations further established that xanthosine drives myoblast proliferation through activation of the ERK/GSK3β/β-catenin signaling cascade.

Together, these findings delineate a liver–muscle metabolic axis in which hepatic CYP1A2-driven caffeine metabolism elevates circulating xanthosine, which in turn acts as a pivotal molecular effector of myogenic growth. This study uncovers a previously unappreciated metabolic mechanism by which hepatic activity orchestrates skeletal muscle development. It also highlights targeted modulation of xanthosine metabolism as a promising strategy to enhance broiler growth performance and production efficiency.

The online version contains supplementary material available at 10.1186/s40104-025-01346-y.