Multiomics-Identified Intervention to Restore Ethanol-Induced Dysregulated Proteostasis and Secondary Sarcopenia in Alcoholic Liver Disease

Abstract

BACKGROUND/AIMS: Signaling and metabolic perturbations contribute to dysregulated skeletal muscle protein homeostasis and secondary sarcopenia in response to a number of cellular stressors including ethanol exposure. Using an innovative multiomics-based curating of unbiased data, we identified molecular and metabolic therapeutic targets and experimentally validated restoration of protein homeostasis in an ethanol-fed mouse model of liver disease. METHODS: Studies were performed in ethanol-treated differentiated C2C12 myotubes and physiological relevance established in an ethanol-fed mouse model of alcohol-related liver disease (mALD) or pair-fed control C57BL/6 mice. Transcriptome and proteome from ethanol treated-myotubes and gastrocnemius muscle from mALD and pair-fed mice were analyzed to identify target pathways and molecules. Readouts including signaling responses and autophagy markers by immunoblots, mitochondrial oxidative function and free radical generation, and metabolic studies by gas chromatography-mass spectrometry and sarcopenic phenotype by imaging. RESULTS: Multiomics analyses showed that ethanol impaired skeletal muscle mTORC1 signaling, mitochondrial oxidative pathways, including intermediary metabolite regulatory genes, interleukin-6, and amino acid degradation pathways are β-hydroxymethyl-butyrate targets. Ethanol decreased mTORC1 signaling, increased autophagy flux, impaired mitochondrial oxidative function with decreased tricarboxylic acid cycle intermediary metabolites, ATP synthesis, protein synthesis and myotube diameter that were reversed by HMB. Consistently, skeletal muscle from mALD had decreased mTORC1 signaling, reduced fractional and total muscle protein synthesis rates, increased autophagy markers, lower intermediary metabolite concentrations, and lower muscle mass and fiber diameter that were reversed by β-hydroxymethyl-butyrate treatment. CONCLUSION: An innovative multiomics approach followed by experimental validation showed that β-hydroxymethyl-butyrate restores muscle protein homeostasis in liver disease.

Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases

“…Several other amino acid-based treatments have been studied in patients with cirrhosis, but there is currently insufficient patient-level evidence to definitively support their use for management of malnutrition, frailty, or sarcopenia in this population. These include ß-hydroxyß-methylbutyrate (a metabolite of leucine), (230,231) acetyl-L-carnitine (an amino acid that has been shown to reduce blood ammonia levels), (193) and L-ornithine L-aspartate (a combination of two endogenous amino acids that reduces blood ammonia levels). (232) timing of Nutritional Intake Timing of nutritional intake is essential to manage nutritional status in patients with cirrhosis.…”

Integrated multiomics analysis identifies molecular landscape perturbations during hyperammonemia in skeletal muscle and myotubes

“…A potential approach to determining therapeutic molecules when there are differences between multiomics analyses is to experimentally validate target molecules or pathways by loss-of-function or gain-of-function studies. Such an approach was recently reported by us in two muscle model systems ( 54 , 55 ). The discord on vertical and horizontal integrations observed in our studies is a potential explanation for unbiased data-based observations not consistently reproduced experimentally.…”

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“…The above formula reflects the change of edge corner area S x in the calculation of reflective characteristics [ 11 ]. The window period change S c is [ 12 ] …”