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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 22, n. 4 FEB 2021.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 15/04090-0 - Identificação e caracterização de mecanismos envolvidos no controle de massa e regeneração do músculo estriado esquelético
• Beneficiário: Anselmo Sigari Moriscot
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/06819-8 - Impacto da ação de MuRF-1 e MuRF-2 na atrofia muscular esquelética durante hipertireoidismo experimental
• Beneficiário: André Cruz de Oliveira
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto