# Excessive DAO inhibits myoblast migration, leading to impaired myotube fusion and muscle strength decline by reducing ECM

## TL;DR

High levels of DAO in the blood are linked to weaker muscles in older people, and this happens by blocking muscle cell movement and fusion through a specific pathway.

## Contribution

This study experimentally shows that excessive DAO impairs muscle function via the Fbln1/FAK pathway, revealing a novel metabolic-biomechanical uncoupling mechanism.

## Key findings

- Elderly males with low grip strength had significantly higher serum DAO levels.
- DAO inhibits myoblast migration and fusion without affecting cell viability in C2C12 cells.
- DAO binds to Fbln1 and suppresses FAK phosphorylation, disrupting cytoskeletal remodeling.

## Abstract

The molecular mechanisms underlying muscle strength decline, particularly in age-related conditions such as sarcopenia, remain poorly understood. Previous omics studies have suggested a potential association between AOC1 (encoding diamine oxidase, DAO, mainly expressed in intestine) and muscle weakness, but experimental validation and mechanistic insights are lacking. This study aims to investigate the influence of secretory DAO on muscle function and its potential receptors.

Serum DAO levels were measured in elderly participants (n = 129) using ELISA and correlated with grip strength. Animal models included naturally aging C57 mice, rapidly aging SAMP8 mice, and a glycerol-induced acute muscle injury model were established to verify the role and content of DAO under overall condition. In vitro studies used C2C12 myoblasts treated with recombinant human DAO to assess migration, fusion, and cytotoxicity. Mechanistic insights were explored via mass spectrometry, co-immunoprecipitation, Western blotting, and immunofluorescence.

Elderly males with low grip strength exhibited significantly higher serum DAO levels, while no such correlation was observed in females. Aged and injured mouse models showed elevated DAO content in skeletal muscle, accompanied by fast-twitch fiber loss. In C2C12 cells, adding DAO recombinant protein inhibited myoblast migration and fusion without affecting viability. Mechanistically, DAO bound to Fbln1, suppressed FAK phosphorylation (Y576/Y577), and disrupted cytoskeletal remodeling.

This study provides experimental evidence that exssive DAO impairs muscle strength by inhibiting myoblast migration and fusion via the Fbln1/FAK pathway. The findings reveal a potential regulation between different organs and cells, and highlight a novel metabolic-biomechanical uncoupling mechanism linked by DAO in sarcopenia.