PMID- 33672385
OWN - NLM
STAT- MEDLINE
DCOM- 20210601
LR  - 20240226
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 4
DP  - 2021 Feb 23
TI  - Regulation of Glucose Metabolism by MuRF1 and Treatment of Myopathy in Diabetic 
      Mice with Small Molecules Targeting MuRF1.
LID - 10.3390/ijms22042225 [doi]
LID - 2225
AB  - 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.
FAU - Labeit, Siegfried
AU  - Labeit S
AUID- ORCID: 0000-0002-9009-210X
AD  - Department of Anesthesiology, Medical Faculty Mannheim, University of Heidelberg, 
      68169 Mannheim, Germany.
AD  - Myomedix GmbH, 69151 Neckargemund, Germany.
FAU - Hirner, Stephanie
AU  - Hirner S
AD  - Department of Anesthesiology, Medical Faculty Mannheim, University of Heidelberg, 
      68169 Mannheim, Germany.
FAU - Bogomolovas, Julijus
AU  - Bogomolovas J
AUID- ORCID: 0000-0001-8344-1909
AD  - Zentralinstitut fur Seelische Gesundheit, 68159 Mannheim, Germany.
FAU - Cruz, Andre
AU  - Cruz A
AUID- ORCID: 0000-0001-7977-8752
AD  - Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, 
      05508-000 Sao Paulo, Brazil.
FAU - Myrzabekova, Moldir
AU  - Myrzabekova M
AD  - Scientific Research Institute of Biology and Biotechnology Problems, al-Farabi 
      Kasakh National University, Almaty 050040, Kazakhstan.
FAU - Moriscot, Anselmo
AU  - Moriscot A
AUID- ORCID: 0000-0003-3098-4613
AD  - Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, 
      05508-000 Sao Paulo, Brazil.
FAU - Bowen, Thomas Scott
AU  - Bowen TS
AD  - School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
FAU - Adams, Volker
AU  - Adams V
AUID- ORCID: 0000-0002-7955-7324
AD  - Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center 
      Dresden, 01307 Dresden, Germany.
AD  - Dresden Cardiovascular Research Institute and Core Laboratories GmbH, 01307 
      Dresden, Germany.
LA  - eng
GR  - MR/S025472/1/MRC_/Medical Research Council/United Kingdom
GR  - 13CVD04/Fondation Leducq/
GR  - 645648/Horizon 2020/
PT  - Journal Article
DEP - 20210223
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Blood Glucose)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (FoxO3 protein, mouse)
RN  - 0 (Muscle Proteins)
RN  - 0 (Tripartite Motif Proteins)
RN  - 0 (muscle RING finger 2 protein, mouse)
RN  - EC 2.3.2.27 (Trim63 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Blood Cell Count
MH  - Blood Glucose/*metabolism
MH  - Carbohydrate Metabolism/genetics
MH  - Diabetes Mellitus, Experimental/*complications/metabolism
MH  - Forkhead Box Protein O3/metabolism
MH  - Hyperglycemia/genetics/therapy
MH  - Lipid Metabolism/genetics
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Molecular Targeted Therapy
MH  - Muscle Proteins/genetics/*metabolism
MH  - Muscular Diseases/*drug therapy/etiology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Tripartite Motif Proteins/genetics/*metabolism
MH  - Ubiquitin-Protein Ligases/genetics/*metabolism
MH  - Mice
PMC - PMC7926706
OTO - NOTNLM
OT  - MuRF1
OT  - MuRF2
OT  - chemical biology
OT  - diabetes mellitus
OT  - glucose and muscle metabolism
COIS- V.A. and S.L. have filed IPRs for the compounds and their possible applications.
EDAT- 2021/03/07 06:00
MHDA- 2021/06/02 06:00
PMCR- 2021/02/23
CRDT- 2021/03/06 01:13
PHST- 2020/10/15 00:00 [received]
PHST- 2021/02/13 00:00 [revised]
PHST- 2021/02/15 00:00 [accepted]
PHST- 2021/03/06 01:13 [entrez]
PHST- 2021/03/07 06:00 [pubmed]
PHST- 2021/06/02 06:00 [medline]
PHST- 2021/02/23 00:00 [pmc-release]
AID - ijms22042225 [pii]
AID - ijms-22-02225 [pii]
AID - 10.3390/ijms22042225 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Feb 23;22(4):2225. doi: 10.3390/ijms22042225.