2. Academic Validation
  3. Regulation of Glucose Metabolism by MuRF1 and Treatment of Myopathy in Diabetic Mice with Small Molecules Targeting MuRF1

Regulation of Glucose Metabolism by MuRF1 and Treatment of Myopathy in Diabetic Mice with Small Molecules Targeting MuRF1

  • Int J Mol Sci. 2021 Feb 23;22(4):2225. doi: 10.3390/ijms22042225.
Siegfried Labeit 1 2,  Stephanie Hirner 1,  Julijus Bogomolovas 3,  André Cruz 4,  Moldir Myrzabekova 5,  Anselmo Moriscot 4,  Thomas Scott Bowen 6,  Volker Adams 7 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Medical Faculty Mannheim, University of Heidelberg, 68169 Mannheim, Germany.
  • 2 Myomedix GmbH, 69151 Neckargemünd, Germany.
  • 3 Zentralinstitut für Seelische Gesundheit, 68159 Mannheim, Germany.
  • 4 Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, 05508-000 Sao Paulo, Brazil.
  • 5 Scientific Research Institute of Biology and Biotechnology Problems, al-Farabi Kasakh National University, Almaty 050040, Kazakhstan.
  • 6 School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
  • 7 Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany.
  • 8 Dresden Cardiovascular Research Institute and Core Laboratories GmbH, 01307 Dresden, Germany.
PMID: 33672385 DOI: 10.3390/ijms22042225
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.

Keywords

MuRF1; MuRF2; chemical biology; diabetes mellitus; glucose and muscle metabolism.

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