A small volatile bacterial molecule triggers mitochondrial dysfunction in murine skeletal muscle

Area of Science:

• Microbiology
• Cell Biology
• Metabolic Disease

Background:

• Mitochondria are crucial in host defense and metabolic regulation.
• Pseudomonas aeruginosa produces 2-amino acetophenone (2-AA), a signaling molecule implicated in chronic infections like cystic fibrosis.
• 2-AA may disrupt host skeletal muscle function, contributing to insulin resistance and disease persistence.

Purpose of the Study:

• To investigate the effects of 2-amino acetophenone (2-AA) on skeletal muscle.
• To determine if 2-AA induces mitochondrial dysfunction and insulin resistance in skeletal muscle.
• To elucidate the molecular mechanisms underlying 2-AA's impact on muscle physiology.

Main Methods:

• High-resolution magic-angle-spinning (HRMAS) proton NMR metabolomics.
• In vivo phosphorus-31 NMR.
• Whole-genome expression analysis.
• Functional muscle studies in mice injected with 2-AA.

Main Results:

• 2-AA induced an insulin resistance signature in mouse skeletal muscle.
• Altered insulin signaling, glucose transport, and mitochondrial function were observed.
• Downregulation of key metabolic genes (Glut4, IRS1, PGC1) and reduced ATP synthesis rate were noted, alongside UCP3 upregulation.
• Muscle function studies confirmed impaired energy production.

Conclusions:

• 2-AA acts as an interkingdom signal, mediating skeletal muscle mitochondrial dysfunction and insulin resistance.
• Reduced energy production in skeletal muscle may promote pathogen persistence and chronic infections.
• These findings highlight 2-AA's role in linking infection, metabolic dysfunction, and host tolerance.