Comprehensive Transcriptome Profiling of NAFLD- and NASH-Induced Skeletal Muscle Dysfunction

Abstract

Nonalcoholic fatty liver disease (NAFLD), characterized by extensive triglyceride accumulation in hepatocytes, may progress to nonalcoholic steatohepatitis (NASH) with liver fibrosis and inflammation and increase the risk of cirrhosis, cancer, and death. It has been reported that physical exercise is effective in ameliorating NAFLD and NASH, while skeletal muscle dysfunctions, including lipid deposition and weakness, are accompanied with NAFLD and NASH. However, the molecular characteristics and alterations in skeletal muscle in the progress of NAFLD and NASH remain unclear. In the present study, we provide a comprehensive analysis on the similarity and heterogeneity of quadriceps muscle in NAFLD and NASH mice models by RNA sequencing. Importantly, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analysis revealed that NAFLD and NASH led to impaired glucose and lipid metabolism and deteriorated functionality in skeletal muscle. Besides this, we identified that myokines possibly mediate the crosstalk between muscles and other metabolic organs in pathological conditions. Overall, our analysis revealed a comprehensive understanding of the molecular signature of skeletal muscles in NAFLD and NASH, thus providing a basis for physical exercise as an intervention against liver diseases.

The regulatory role of metabolic organ-secreted factors in the nonalcoholic fatty liver disease and cardiovascular disease

“…Irisin, IL-6 and myostatin are the most extensively studied myokines in NAFLD, and serum irisin and IL-6 levels and muscle irisin and IL-6 expression are significantly elevated in exercised NAFLD or NASH mouse models ( 59 , 142 ). Limited evidence proposed that irisin had the properties of promoting muscle hypertrophy, enhancing insulin sensitivity, alleviating hepatic steatosis and anti-inflammation, and improving metabolic syndrome and CVD, but the underlying mechanism still needs further characterization ( 142 , 143 ). IL-6 derived from myocytes has been reported to mediate glucose homeostasis, white adipose tissue lipolysis, and inflammatory reaction, as it stimulates the release of IL-10, which creates an anti-inflammatory environment ( 142 ).…”

Discussing the role of circular RNA in the pathogenesis of non-alcoholic fatty liver disease and its complications

“…Despite the multiplication of potential new drug candidates and clinical trials, there is still no approved treatment for NASH, justifying the urge of a finding ( 17 ). The last few years have been critical for the elucidation of new pathways involved in liver diseases pathophysiology, thanks, notably, to the democratization of new breakthrough methods in the field of metabolomics, proteomics and transcriptomics, opening the way to new therapeutic hopes ( 18 – 20 ). Among these new emerging subjects, non-coding RNAs and their pleiotropic roles in chronic liver diseases has been widely studied ( 21 , 22 ).…”