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.