Mechanistic basis of exercise responses in liver disease

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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 mechanistic basis of responses to EE or RE while enhancing compliance in patients with cirrhosis to develop targeted and personalized training programs.