Hyperglycemia Induces Skeletal Muscle Atrophy via a WWP1/KLF15 Axis

JCI Insight. 2019 Feb 21;4(4):e124952. doi: 10.1172/jci.insight.124952.

Abstract

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.

Keywords: Diabetes; Metabolism; Muscle; Muscle Biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / administration & dosage
  • COS Cells
  • Chlorocebus aethiops
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / drug therapy
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Glucosides / administration & dosage
  • HEK293 Cells
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / chemically induced
  • Hyperglycemia / complications*
  • Hyperglycemia / drug therapy
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / etiology
  • Muscular Atrophy / genetics
  • Muscular Atrophy / pathology*
  • Muscular Atrophy / prevention & control
  • Proteolysis
  • Signal Transduction / genetics
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage
  • Streptozocin / toxicity
  • Ubiquitin-Protein Ligases / metabolism*
  • Up-Regulation

Substances

  • Benzhydryl Compounds
  • Glucosides
  • Klf15 protein, mouse
  • Kruppel-Like Transcription Factors
  • Sodium-Glucose Transporter 2 Inhibitors
  • Streptozocin
  • WWP1 protein, mouse
  • Ubiquitin-Protein Ligases
  • empagliflozin