Exercise Training Decreases Alcohol Consumption and Tissue Injury by an FGF21-dependent Mechanism

Alcohol use disorder is a major driver of continued liver injury in alcohol-related liver disease. Patients with ALD also commonly develop sarcopenia, impaired skeletal muscle function, fatigue, mitochondrial dysfunction, reduced exercise capacity, and physical frailty. Exercise may improve muscle and metabolic function and may also reduce alcohol craving and consumption. FGF21 has been proposed as a mechanistic link among exercise, skeletal muscle, liver injury, metabolism, and alcohol-related behavior.

This is a randomized, controlled, unblinded study of 30 adults with AUD/ALD. Participants will be randomized 1:1 to endurance exercise plus standard of care (EE+SOC) or standard of care alone (SOC). Participants assigned to EE+SOC will complete a 12-week home-based supervised cycling program three days per week, with a target of approximately 60 minutes per session and intensity adjusted for safety, tolerance, and beta-blocker use. Exercise sessions will be remotely monitored, and fitness testing will occur at Cleveland Clinic. Participants in the SOC arm will continue usual clinical care and their usual physical activity without the structured exercise intervention.

The study will assess alcohol consumption and craving; circulating and skeletal muscle FGF21; liver injury measures; exercise capacity and physical performance; body composition; fatigue; skeletal muscle metabolism and mitochondrial function; and exploratory transcriptomic, proteomic, metabolomic, microbiome, amino acid, protein synthesis, TCA intermediate, and cell-signaling responses.

Inclusion criteria

• • Adults age 18 years or older, of either sex.

• Clinical diagnosis of alcohol use disorder (AUD) / alcohol-related liver disease (ALD).
• Meets NIAAA hazardous-drinking criteria: at least 7 drinks/week for women or 14 drinks/week for men for more than 6 months, with ongoing alcohol use within 2 months of evaluation.
• MELD score less than 21.
• Able to safely participate in exercise testing and endurance exercise.
• Able to provide informed consent.
• No concurrent renal, cardiac, pulmonary, cerebrovascular, or malignant illness that affects skeletal muscle mass; no diabetes mellitus; and no use of medications that affect skeletal muscle mass/protein turnover as described in the protocol, including anabolic steroids, high-dose corticosteroids, or anticoagulants.

Exclusion criteria

• • Pedal edema above the ankle or grade 2 pedal edema.

• Liver transplant.
• Active malignancy.
• Gastrointestinal bleed within the previous 4 weeks.
• Hepatic encephalopathy within the previous 6 months.
• Grade 2 or greater active esophageal varices.
• Active infection.
• Large ascites by clinical and/or imaging criteria.
• Advanced cardiac disease (NYHA class 3 or 4) or advanced pulmonary disease (GOLD class 3 or 4).
• Use of medications affecting muscle protein turnover, including corticosteroids, or medications used to prevent clotting.
• Prior orthopedic surgery or chronic joint pain that, in the opinion of the PI, may inhibit participation.
• INR greater than 1.7 or platelet count less than 60,000/mL.
• Unable to provide informed consent; judged likely to be unable to perform exercise or unlikely to complete the study in the opinion of the investigators.
• End-stage kidney disease defined as eGFR less than 15 mL/min/1.73 m² or dialysis.
• Considered unsafe for exercise in the opinion of the PI.
• Failure to pass the exercise stress test.