| Full text | |
| Author(s): |
Labeit, Siegfried
[1, 2]
;
Hirner, Stephanie
[2]
;
Bogomolovas, Julijus
[3]
;
Cruz, Andre
[4]
;
Myrzabekova, Moldir
[5]
;
Moriscot, Anselmo
[4]
;
Bowen, Thomas Scott
[6]
;
Adams, Volker
[7, 8, 9]
Total Authors: 8
|
| Affiliation: | [1] Myomedix GmbH, D-69151 Neckargemund - Germany
[2] Heidelberg Univ, Med Fac Mannheim, Dept Anesthesiol, D-68169 Mannheim - Germany
[3] Zentralinst Seel Gesundheit, D-68159 Mannheim - Germany
[4] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, BR-05508000 Sao Paulo - Brazil
[5] Al Farabi Kasakh Natl Univ, Sci Res Inst Biol & Biotechnol Problems, Alma Ata 050040 - Kazakhstan
[6] Univ Leeds, Sch Biomed Sci, Leeds LS2 9JT, W Yorkshire - England
[7] Tech Univ Dresden, Lab Mol & Expt Cardiol, Heart Ctr Dresden, D-01307 Dresden - Germany
[8] Dresden Cardiovasc Res Inst, D-01307 Dresden - Germany
[9] Core Labs GmbH, D-01307 Dresden - Germany
Total Affiliations: 9
|
| Document type: | Journal article |
| Source: | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 22, n. 4 FEB 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 15/04090-0 - Identification and caracterization of mechanisms involved in skeletal muscle mass control and regeneration |
| Grantee: | Anselmo Sigari Moriscot |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 19/06819-8 - Impact of MuRF-1 and MuRF-2 to skeletal muscle wasting under experimental hyperthyroidism |
| Grantee: | André Cruz de Oliveira |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate (Direct) |