Skeletal muscle miR-34a/SIRT1:AMPK axis is activated in experimental and human non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) pathogenesis associates with intramyocellular lipid deposition and mitochondrial dysfunction. microRNAs (miRs), including pro-apoptotic miR-34a, are modulated during disease progression in liver tissue and plasma. We aimed to investigate the functional role of the miR-34a/SIRT1:AMP-activated protein kinase (AMPK) pathway in modulating local mitochondrial dysfunction in the skeletal muscle of human and experimental non-alcoholic steatohepatitis. Muscle biopsies were obtained from morbid obese NAFLD patients undergoing bariatric surgery. C57BL/6N mice were fed different NAFLD-inducing diets and C2C12 muscle cells incubated with palmitic acid (PA) in the presence or absence of an AMPK activator, or upon miR-34a functional modulation. Several muscle miRNAs, including miR-34a, were found increased with human NAFLD progression. Activation of the miR-34a/SIRT1:AMPK pathway, concomitant with impairment in insulin signalling mediators and deregulation of mitochondrial-shaping proteins, was evident in C2C12 cells incubated with PA, as well as in the skeletal muscle of all three diet-induced NAFLD mice models. Functional studies established the association between miR-34a- and PA-induced muscle cell deregulation. Of note, activation of AMPK almost completely prevented miR-34a- and PA-induced cellular stress. In addition, the miR-34a/SIRT1:AMPK pathway and mitochondrial dynamics dysfunction were also found amplified in muscle of human NAFLD. Finally, muscle miR-34a expression and mitofusin 2 (Mfn2) protein levels correlated with hallmarks of NAFLD and disease progression. Our results indicate that activation of the miR-34a/SIRT1:AMPK pathway leads to mitochondrial dynamics dysfunction in skeletal muscle of human and experimental NAFLD, representing an appealing prospective target in metabolic syndrome. Key messages Skeletal muscle microRNAs are modulated during NAFLD progression. Palmitic acid-induced muscle cell dysfunction occurs, at least in part, through activation of the miR-34a/SIRT1:AMPK pathway. miR-34a/SIRT1:AMPK activation associates with mitochondria dynamics dysfunction in human NAFLD.