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Knockout of the Muscle-Specific E3 Ligase MuRF1 Affects Liver Lipid Metabolism upon Dexamethasone Treatment in Mice
Laurent Mosoni1, Arno Germond2, Cécile Coudy-Gandilhon1
1Université Clermont Auvergne, INRAE, UNH, Unité de Nutrition Humaine, F-63000 Clermont-Ferrand, France.
Abstract:
In order to preserve muscle mass during catabolic states, investigators are actively searching for a specific inhibitor of MuRF1, the only known E3 ligase that can target muscle contractile proteins for their degradation. However, what would be the consequences of such inhibitors on other organs, both in the short and long term? Indeed, skeletal muscles can provide amino acids for liver gluconeogenesis, which is a crucial adaptation for maintaining glucose homeostasis upon elevated energy demands (e.g., during prolonged starvation). Comparing 3-month-old wild-type and MuRF1-KO mice, we measured tissue weights, liver glycogen, lipid and protein content, and liver biochemical composition using Fourier transform infrared (FTIR) spectrometry in control animals and in dexamethasone (Dex)-treated animals. Dex induces a catabolic situation with muscle atrophy and lipid deposits in the liver. In response to Dex treatment, liver glycogen, lipid, and protein content increased in wild type (WT) and MuRF1-KO mice. We found that MuRF1 deletion differentially affected organ weights, the liver of KO mice being hypertrophied upon Dex treatment when compared to WT mice. Upon Dex treatment, muscle mass was preserved in MuRF1-KO mice, and by contrast, liver lipid content increased more in these animals than in WT mice. PLS-DA analysis of FTIR showed that the levels of 13 markers were significantly altered in KO vs WT mice, witnessing profound alterations of lipid, protein, and glycogen content in the liver due to the absence of MuRF1. Using Nile red and oil red lipid staining, we also found that both membrane-linked lipids and intracellular lipid droplets were altered due to the absence of MuRF1. Altogether, it seems that when the liver is deprived of the possibility of obtaining amino acids from muscle upon Dex treatment, there is a concomitant increase in tissue weight and anabolic activity.
Insights
Inhibiting MuRF1 preserves muscle mass but causes liver hypertrophy and increased lipid accumulation in mice during catabolic states. This highlights potential trade-offs when blocking muscle protein degradation.
Area of Science:
- Molecular biology and physiology
- Metabolic regulation
- Muscle and liver interactions
Background:
- Muscle RING Finger 1 (MuRF1) is a key E3 ligase targeting muscle contractile proteins for degradation during catabolic states.
- Skeletal muscle provides amino acids for liver gluconeogenesis, essential for glucose homeostasis during prolonged energy demands.
- Inhibiting MuRF1 is explored to preserve muscle mass, but its systemic effects, particularly on the liver, are not fully understood.
Purpose of the Study:
- To investigate the consequences of MuRF1 deficiency on liver metabolism and organ adaptation during a catabolic state induced by dexamethasone (Dex).
- To compare the effects of Dex treatment on wild-type (WT) and MuRF1-knockout (KO) mice, focusing on muscle mass preservation and liver composition.
Main Methods:
- Comparison of 3-month-old WT and MuRF1-KO mice.
- Dexamethasone (Dex) administration to induce a catabolic state.
- Measurement of tissue weights, liver glycogen, lipid, and protein content.
- Fourier transform infrared (FTIR) spectrometry and PLS-DA analysis for liver biochemical composition.
- Lipid staining (Nile red, oil red) to assess lipid alterations.
Main Results:
- MuRF1-KO mice showed preserved muscle mass and hypertrophied livers compared to WT mice after Dex treatment.
- Liver lipid content significantly increased in MuRF1-KO mice compared to WT mice under Dex-induced catabolism.
- FTIR analysis revealed profound alterations in liver lipid, protein, and glycogen content in MuRF1-KO mice.
- Absence of MuRF1 altered both membrane-linked lipids and intracellular lipid droplets in the liver.
Conclusions:
- MuRF1 deficiency preserves muscle mass during catabolic stress but leads to significant liver hypertrophy and altered lipid metabolism.
- The liver compensates for the lack of muscle-derived amino acids by increasing its own anabolic activity and lipid storage.
- Targeting MuRF1 requires careful consideration of its impact on liver function and overall metabolic homeostasis.
