# Mechanistic basis of exercise responses in liver disease

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $275,231

## Abstract

Sarcopenia, or loss of skeletal muscle mass, with impaired contractile function that causes physical frailty and
decreased exercise capacity are frequent in cirrhosis and contribute to adverse clinical outcomes. Exercise
training improves some measures of muscle mass and exercise capacity but the mechanistic basis of these
responses in cirrhosis is not known. In healthy subjects, endurance exercise (EE) improves maximum oxygen
consumption (VO2max) while resistance exercise (RE) increases muscle mass and strength. In patients with
cirrhosis, an increase in muscle mass improves survival. In contrast, higher VO2max is associated with better
survival but whether an increase in VO2max translates to improved clinical outcomes in cirrhosis is not known.
Low adherence to prescribed exercise training is another challenge in patients with cirrhosis and home-based,
unsupervised programs are not consistently effective. Changes in gut microbiome and microbial metabolites
(xenometabolites) occur with exercise in healthy subjects, but whether exercise causes changes in the gut
microbiome/metabolites in cirrhosis and if the changes can be related to skeletal muscle anabolic responses
are also not known. In preliminary studies, we noted that ammonia, a xenometabolite that is increased in the
plasma and skeletal muscle in patients with cirrhosis, causes sarcopenia in preclinical models. In the proposed
studies, we will integrate hypothesis- and data-driven approaches to identify the molecular and metabolic
responses to an exercise training program in patients with cirrhosis to reverse sarcopenia. We will test the
overall hypothesis that a supervised, structured endurance or resistance exercise will result in
improvement in skeletal muscle molecular, metabolic and functional perturbations in cirrhosis. In AIM
1, the molecular and metabolic responses to exercise training in well-characterized, stable patients with
cirrhosis will be determined. Patients will be randomized to a home-based, telemedicine supervised EE or RE
program or standard of care (SOC) management for 12 weeks. Muscle mass, measures of physical frailty,
muscle protein synthesis, mitochondrial function and cellular signaling responses will be quantified. Patients
will be followed for 6-months after completion of the exercise program for mortality, decompensation, and
hospitalization. These first-in-class studies will evaluate the efficacy of a supervised, personalized training
program in patients with cirrhosis. In AIM 2, global multiomics responses will be compared between EE, RE
and SOC. Skeletal muscle transcriptome, proteome, phosphoproteome, metabolome; plasma
proteome/metabolome; and stool microbiome/metabolome will be quantified. An integrated multiomics
approach including functional enrichment analyses will be performed using machine learning algorithms to
relate the muscle and plasma responses to alterations in microbiome in cirrhosis. These studies will
simultaneously help address the mecha...

## Key facts

- **NIH application ID:** 10909351
- **Project number:** 5R01DK133905-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Srinivasan Dasarathy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $275,231
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909351

## Citation

> US National Institutes of Health, RePORTER application 10909351, Mechanistic basis of exercise responses in liver disease (5R01DK133905-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909351. Licensed CC0.

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