Exercise and physical activity in cirrhosis: opportunities or perils

Abstract

Reduced exercise capacity and impaired physical performance are observed in nearly all patients with liver cirrhosis. Physical activity and exercise are physiological anabolic stimuli that can reverse dysregulated protein homeostasis or proteostasis and potentially increase muscle mass and contractile function in healthy subjects. Cirrhosis is a state of anabolic resistance, and unlike the beneficial responses to exercise reported in physiological states, there are few systematic studies evaluating the response to exercise in cirrhosis. Hyperammonemia is a mediator of the liver-muscle axis with net skeletal muscle ammonia uptake in cirrhosis causing signaling perturbations, mitochondrial dysfunction with decreased ATP content, modifications of contractile proteins, and impaired ribosomal function, all of which contribute to anabolic resistance in cirrhosis and have the potential to impair the beneficial responses to exercise. English language-publications in peer-reviewed journals that specifically evaluated the impact of exercise in cirrhosis were reviewed. Most studies evaluated responses to endurance exercise, and readouts included peak or maximum oxygen utilization, grip strength, and functional capacity. Endurance exercise for up to 12 wk is clinically tolerated in well-compensated cirrhosis. Data on the safety of resistance exercise are conflicting. Nutritional supplements enhance the benefits of exercise in healthy subjects but have not been evaluated in cirrhosis. Whether the beneficial physiological responses with endurance exercise and increase in muscle mass with resistance exercise that occur in healthy subjects also occur in cirrhotics is not known. Specific organ-system responses, changes in body composition, or improved long-term clinical outcomes with exercise in cirrhosis need evaluation.

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

“…A number of unanswered questions regarding an exercise program in cirrhosis remain, including the duration, time of day, and impact of concurrent exercise on responses. ( 274 ) Notwithstanding these, it is prudent for patients to optimize their portal hypertensive complications (e.g., ascites control, variceal prophylaxis, optimal HE therapies) before initiating an activity‐based program.…”

Shared and unique phosphoproteomics responses in skeletal muscle from exercise models and in hyperammonemic myotubes

“…We observed that ammonia, a cytotoxin consistently generated during exercise ( Bellar et al., 2020 ; Chen et al., 2020 ; Gorostiaga et al., 2014 ; Graham et al., 1990 , 1993 , 1995 ; Graham and MacLean, 1998 ), results in differential phosphorylation events and enrichment of pathways in myotubes. A number of unique and shared phosphoproteomics responses between myotube hyperammonemia and skeletal muscle from exercise models were identified.…”

“…Because exercise increases muscle ammoniagenesis ( Bellar et al., 2020 ; Calvert et al., 2010 ; Chen et al., 2020 ; Graham and MacLean, 1998 ) and hyperammonemia results in perturbed skeletal muscle proteostasis, we first examined the phosphoproteomics landscape during hyperammonemia in myotubes to determine whether there are post-translational changes that may mediate decreased protein synthesis. In the 6 and 24h hyperammonemic myotube datasets, there were 448 DEpP that were identified in hyperammonemic myotubes with 164 total (75 unique) DEpP in the 6hAmAc treatment group and 373 total (284 unique) DEpP in the 24hAmAc treatment group with 89 shared DEpP ( Figure 1 A).…”

“…Such a strategy has the potential to be applied to study other interventions also. This is of particular interest because despite extensive data on the benefits and responses of exercise training in healthy subjects, in disease states, phenotype and molecular responses are not consistent, and mediators of differential responses have not been well studied ( Bellar et al., 2020 ; McGee and Hargreaves, 2020 ). Therefore, a strategy to determine optimal animal models of exercise that most closely recapitulate the desired study outcomes of exercise in humans is needed ( Feng et al., 2019 ).…”

Wearables, Physical Activity, and Exercise Testing in Liver Disease

“…As yet, very little is understood about the most effective proportions of light and moderate-to-vigorous intensity activity, and of the potential benefits of different forms of physical activity (e.g., aerobic and resistance training) that would best promote desirable outcomes in patients with advanced liver disease. 46 Patients who desire empowerment to take charge of their own health and who appreciate that what needs to be improved needs to be measured with selfmonitoring hold the potential to become a strong force for effective use of wearable activity tracking in hepatology.…”