Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis.
Animals
Benzhydryl Compounds
/ administration & dosage
COS Cells
Chlorocebus aethiops
Diabetes Mellitus, Experimental
/ blood
Down-Regulation
Female
Gene Expression Profiling
Glucosides
/ administration & dosage
HEK293 Cells
Humans
Hyperglycemia
/ blood
Kruppel-Like Transcription Factors
/ genetics
Male
Mice
Mice, Knockout
Muscle, Skeletal
/ drug effects
Muscular Atrophy
/ etiology
Proteolysis
Signal Transduction
/ genetics
Sodium-Glucose Transporter 2 Inhibitors
/ administration & dosage
Streptozocin
/ toxicity
Ubiquitin-Protein Ligases
/ metabolism
Up-Regulation
Diabetes
Metabolism
Muscle
Muscle Biology
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
21 02 2019
21 02 2019
Historique:
received:
17
09
2018
accepted:
16
01
2019
entrez:
5
3
2019
pubmed:
5
3
2019
medline:
12
5
2020
Statut:
epublish
Résumé
Diabetes mellitus is associated with various disorders of the locomotor system including the decline in mass and function of skeletal muscle. The mechanism underlying this association has remained ambiguous, however. We now show that the abundance of the transcription factor KLF15 as well as the expression of genes related to muscle atrophy are increased in skeletal muscle of diabetic model mice, and that mice with muscle-specific KLF15 deficiency are protected from the diabetes-induced decline of skeletal muscle mass. Hyperglycemia was found to upregulate the KLF15 protein in skeletal muscle of diabetic animals, which is achieved via downregulation of the E3 ubiquitin ligase WWP1 and consequent suppression of the ubiquitin-dependent degradation of KLF15. Our results revealed that hyperglycemia, a central disorder in diabetes, promotes muscle atrophy via a WWP1/KLF15 pathway. This pathway may serve as a therapeutic target for decline in skeletal muscle mass accompanied by diabetes mellitus.
Identifiants
pubmed: 30830866
pii: 124952
doi: 10.1172/jci.insight.124952
pmc: PMC6478420
doi:
pii:
Substances chimiques
Benzhydryl Compounds
0
Glucosides
0
Klf15 protein, mouse
0
Kruppel-Like Transcription Factors
0
Sodium-Glucose Transporter 2 Inhibitors
0
Streptozocin
5W494URQ81
WWP1 protein, mouse
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
empagliflozin
HDC1R2M35U
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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