Knockout of the\nMuscle-Specific E3 Ligase MuRF1 Affects\nLiver Lipid Metabolism upon Dexamethasone Treatment in Mice

In order to preserve muscle mass during catabolic states,\ninvestigators\nare actively searching for a specific inhibitor of MuRF1, the only\nknown E3 ligase that can target muscle contractile proteins for their\ndegradation. However, what would be the consequences of such inhibitors\non other organs, both in the short and long term? Indeed, skeletal\nmuscles can provide amino acids for liver gluconeogenesis, which is\na crucial adaptation for maintaining glucose homeostasis upon elevated\nenergy demands (e.g., during prolonged starvation). Comparing 3-month-old\nwild-type and MuRF1-KO mice, we measured tissue weights, liver glycogen,\nlipid and protein content, and liver biochemical composition using\nFourier transform infrared (FTIR) spectrometry in control animals\nand in dexamethasone (Dex)-treated animals. Dex induces a catabolic\nsituation with muscle atrophy and lipid deposits in the liver. In\nresponse to Dex treatment, liver glycogen, lipid, and protein content\nincreased in wild type (WT) and MuRF1-KO mice. We found that MuRF1\ndeletion differentially affected organ weights, the liver of KO mice\nbeing hypertrophied upon Dex treatment when compared to WT mice. Upon\nDex treatment, muscle mass was preserved in MuRF1-KO mice, and by\ncontrast, liver lipid content increased more in these animals than\nin WT mice. PLS-DA analysis of FTIR showed that the levels of 13 markers\nwere significantly altered in KO vs WT mice, witnessing profound alterations\nof lipid, protein, and glycogen content in the liver due to the absence\nof MuRF1. Using Nile red and oil red lipid staining, we also found\nthat both membrane-linked lipids and intracellular lipid droplets\nwere altered due to the absence of MuRF1. Altogether, it seems that\nwhen the liver is deprived of the possibility of obtaining amino acids\nfrom muscle upon Dex treatment, there is a concomitant increase in\ntissue weight and anabolic activity.