Regulation of glucose metabolism by MuRF1 and treatment of myopathy in diabetic mice with small molecules targeting MuRF1
The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
23 February 2021
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| In: |
International journal of molecular sciences
Year: 2021, Volume: 22, Issue: 4, Pages: 1-14 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22042225 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/ijms22042225 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1422-0067/22/4/2225 
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| Author Notes: | Siegfried Labeit, Stephanie Hirner, Julijus Bogomolovas, André Cruz, Moldir Myrzabekova, Anselmo Moriscot, Thomas Scott Bowen and Volker Adams |
| Summary: | The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog. MuRF1 and MuRF2-KO (knockout) mice have elevated serum glucose, elevated triglycerides, and reduced glucose tolerance. In addition, MuRF2-KO mice have a reduced tolerance to a fat-rich diet. Western blot and enzymatic studies on MuRF1-KO skeletal muscle showed perturbed FoxO-Akt signaling, elevated Akt-Ser-473 activation, and downregulated oxidative mitochondrial metabolism, indicating potential mechanisms for MuRF1,2-dependent glucose and fat metabolism regulation. Consistent with this, the adenoviral re-expression of MuRF1 in KO mice normalized Akt-Ser-473, serum glucose, and triglycerides. Finally, we tested the MuRF1/2 inhibitors MyoMed-205 and MyoMed-946 in a mouse model for type 2 diabetes mellitus (T2DM). After 28 days of treatment, T2DM mice developed progressive muscle weakness detected by wire hang tests, but this was attenuated by the MyoMed-205 treatment. While MyoMed-205 and MyoMed-946 had no significant effects on serum glucose, they did normalize the lymphocyte-granulocyte counts in diabetic sera as indicators of the immune response. Thus, small molecules directed to MuRF1 may be useful in attenuating skeletal muscle strength loss in T2DM conditions. |
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| Item Description: | Gesehen am 03.05.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22042225 |