Metabolic reprogramming during hyperammonemia targets mitochondrial function and postmitotic senescence.

Area of Science:

• Biochemistry
• Cell Biology
• Physiology

Background:

• Ammonia is a cytotoxic metabolite impacting cellular function and inducing senescence.
• Skeletal muscle plays a key role in ammonia uptake and disposal during chronic diseases.
• Mitochondrial dysfunction is implicated in various pathologies, including senescence.

Purpose of the Study:

• To investigate the mitochondrial oxidative defects and functional consequences of hyperammonemia in skeletal muscle.
• To elucidate the molecular mechanisms underlying ammonia-induced senescence in muscle cells.
• To assess the reversibility of these perturbations upon ammonia lowering.

Main Methods:

• Multiomics approaches (transcriptomics, proteomics) integrated with functional and metabolic studies.
• Analysis of myotubes and hyperammonemic rat muscle (portacaval anastomosis model).
• Experimental validation of multiomics data and assessment of senescence markers.

Main Results:

• Hyperammonemia induced distinct temporal responses, including oxidative dysfunction and senescence pathways.
• Observed mitochondrial defects: impaired electron transport chain complexes, reduced ATP synthesis, increased free radicals.
• Demonstrated senescence-associated molecular phenotype: increased β-galactosidase activity and expression of p16INK, p21, and p53.

Conclusions:

• Dysregulated ammonia metabolism causes reversible mitochondrial dysfunction and a specific skeletal muscle senescence phenotype.
• Transcriptional and translational perturbations underlie these effects.
• Ammonia lowering partially reverses mitochondrial dysfunction and senescence markers in skeletal muscle.