Document text
Principal Investigator: Srinivasan Dasarathy
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2024
Award: $275,231
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <AI system><ATP Synthesis><ATP Synthesis Pathway><Address><Adherence><Ammonia><Artificial Intelligence><Autophagocytosis><Blood Plasma><Body Tissues><Cell Communication and Signaling><Cell Signaling><Chronic Disease><Chronic Illness><Cirrhosis><Clinical><Clinical Trials><Computer Reasoning><Data><Disease><Disorder><Evaluation><Exercise><Fatigue><Feces><Foundations><Free Radicals><Future><GI microbiome><Generations><Global Change><Goals><Hepatic><Hepatic Cirrhosis><Hepatic Disorder><Home><Hospital Admission><Hospitalization><Human><Hyperammonemia><Impairment><Intermediary Metabolism><Intracellular Communication and Signaling><Kinetics><Lack of Energy><Liver Cirrhosis><Liver diseases><Machine Intelligence><Machine Learning><Measures><Mediator><Metabolic><Metabolic Processes><Metabolism><Methods><Microbiomics><Mission><Mitochondria><Modern Man><Molecular><Multi-center studies><Multicenter Studies><Multiomic Data><Muscle><Muscle Atrophy><Muscle Mitochondria><Muscle Proteins><Muscle Tissue><Muscular Atrophy><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Outcome><Oxygen Consumption><Patients><Phosphorylation><Plasma><Plasma Serum><Pre-Clinical Model><Preclinical Models><Prescribed exercise><Protein Biosynthesis><Protein Phosphorylation><Proteome><Proteomics><Protocol><Protocols documentation><Publishing><Randomized><Recommendation><Reporting><Reticuloendothelial System, Serum, Plasma><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Safety><Sarcosomes><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><Structure><Systems Biology><Telemedicine><Testing><Tissues><Tracer><Training><Training Programs><Translating><VO2 max><VO2max><Voluntary Muscle><autophagy><biological signal transduction><chronic disorder><cirrhotic><decreased muscle mass><decreased muscle strength><determine efficacy><digestive tract microbiome><dynapenia><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><endurance exercise><enteric microbiome><evaluate efficacy><examine efficacy><exercise capacity><exercise prescription><exercise program><exercise training><fecal microbiome><fitness program><frailty><gastrointestinal microbiome><global gene expression><global transcription profile><gut dysbiosis><gut microbiome><gut-associated microbiome><hepatic disease><hepatopathy><homes><improved><innovate><innovation><innovative><intestinal biome><intestinal microbiome><liver disorder><low muscle mass><low muscle strength><machine based learning><machine learned algorithm><machine learning algorithm><machine learning based algorithm><maximal oxygen uptake><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><microbial><microbiome><microbiome research><microbiome science><microbiome studies><mitochondrial><mitochondrial oxidative dysfunction><mortality><multiomics><multiple omic data><multiple omics><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle strength><muscle strength decline><muscle wasting><muscular><panomics><programs><prospective><protein homeostasis><protein synthesis><proteostasis><randomisation><randomization><randomly assigned><reduced muscle mass><reduced muscle strength><resistance exercise><resistance training><response><sarcopenia><sarcopenic><skeletal muscle atrophy><skeletal muscle breakdown><skeletal muscle loss><skeletal muscle protein loss><skeletal muscle wasting><standard of care><stool><stool microbiome><stool-associated microbiome><transcriptome><transcriptomics>