Sarcopenia is a frequent complication in the natural history of cirrhosis caused by inadequate energy intake, rapid transition to a fasting state, alterations in energy substrates utilization, impairment of protein synthesis and increased muscle catabolism. Hepatic encephalopathy (HE), a syndrome of brain dysfunction caused by liver failure and/or portal-systemic shunting , is also frequent in cirrhotic patients . HE is related to a series of relevant outcomes both for patients and for caregivers: further decompensation, mortality, low quality of life, high risk of falls , having a relevant impact on patient's social life and healthcare services.
The relationship between muscle alteration and cognitive impairment in cirrhosis is actually under debate. Therefore, it appears intriguing and interesting to investigate the interaction between minimal HE, assessed by psychometric tests and also using a series of biomedical instruments able to study movement alterations, and impairment of muscle mass and function evaluated by imaging and a physical performance battery test. An experimental study to investigate the liver muscle axis in these patients will also be performed on cultured human mioblast. Two clinical units and one experimental unit will carry on the project aimed to study:
-kinematic and kinetic parameters in subjects with and without MHE;
the correlation between kinematic and kinetic alterations, indexes of dynamic stability, with muscle mass and/or performance ;
-the ability of kinematic and kinetic parameters vs parameters of muscle mass and/or performance in identifying cirrhotic subjects at risk of falls, OHE-development, hospitalization, death during 6 months follow up;
-whether liver-derived exosomes, isolated from plasma samples of cirrhotic patients with MHE, or with sarcopenia, or with altered kinematic and kinetic parameters could vehicle, to skeletal muscle, microRNAs able to induce or contribute to muscle alterations.
The relationship between muscular alteration and cognitive impairment in cirrhosis is actually under debate. Infact, a series of consequences, such as falls and related injuries could have a deep impact both on patient, and caregiver as well as on healthcare services. Therefore, it appears intriguing and interesting to evaluate, also by using a series of biomedical instruments able to study a variety of movement alterations, as well as the search of MHE by psychometric tests and of muscular impairment by CT scan.
To date, although several key factors contributing to muscle wasting are known, the molecular mechanisms causing sarcopenia in cirrhosis still remain poorly elucidated; in particular mediators of the liver-muscle axis have not yet been clearly identified.
Emerging evidences suggest that hepatic physiological and pathological events are regulated by extracellular vesicles (EVs), that are intercellular mediators of cell-to-cell communication. Their capability of communicating with neighboring or distant cells delivering their cargo, sustains cellular cross-talk within liver and between liver and different organs and tissues (15, 16). EVs from injured hepatocytes can target several cell types in liver and promote liver cirrhosis establishment; on the other hand they are massively released from cirrothic liver into the bloodstream, inducing pathogenic processes in remote organs (10).
Therefore, given the close metabolic interplay between skeletal muscle and liver, the ability of muscle cells to uptake exosomes and the key role of miRNA molecules to regulate muscle homeostasis, the present study is the first to investigate the possibility that EVs released from cirrhotic liver, vehicle to muscle tissue microRNAs able to contribute to sarcopenia. The proposed experimental in vitro model is a strategic tool to directly evaluate whether exosomes, isolated from plasma samples of cirrhotic patients with minimal HE, are able to interfere, carrying a specific miRNA cargo, with the differentiation and the protein homeostasis of human muscle culture.
Therefore, the study will have a direct impact in elucidating the molecular mechanism underlying sarcopenia in liver diseases and in particular in identifying novel mediators of the liver-muscle axis. Finally the identification of the microRNAs responsible for muscle atrophic processes in liver disease might provide a great insight into therapeutic strategies for sarcopenia, such as by inhibiting secretion or fusion of exosomes with muscle cells, or by using miRNA inhibitor or AntagomiR.