Comparative multi-omics in female mice reveals tissue-specific vulnerabilities to chronic alcohol intake.

BACKGROUND

Alcohol-related liver disease (ALD) and alcohol-related myopathy are consequences of chronic alcohol use. However, understanding of the associated molecular mechanisms and effective treatments remains limited.

METHODS

Multi-omics were employed to uncover molecular blueprints of liver versus skeletal muscle responses to chronic alcohol exposure, using a preclinical mouse model showing signs of alcohol-related liver dysregulation (diminished liver phosphatidylcholine-to-phosphatidylethanolamine lipid ratio) and alcohol-related myopathy (reduced muscle mass and strength).

RESULTS

A greater proportion of transcriptomic, proteomic, and metabolomic features were altered by alcohol in liver than muscle, whereas similar proportions of lipid species were affected in both tissues. The liver was significantly enriched for a broad and diverse set of metabolic pathways across molecular layers, while muscle was associated with upregulated inflammatory and matrisome responses and impaired mitochondrial energetics. Lipidome analyses also revealed a novel potential role for altered phospholipid remodeling in the etiology of alcohol-related myopathy. Finally, computational drug repurposing identified several compounds for therapeutic targeting of alcohol-induced liver (e.g., saracatinib, GSK126) and muscle (e.g., metformin, trichostatin A) pathophysiology.

CONCLUSIONS

Overall, this study provides a list of therapeutic targets and treatments to help expedite the understanding of and countermeasures against ALD and myopathy in humans.