Mechanism of induction of muscle protein loss by hyperglycaemia

Steve T. Russell, Seema Rajani, Raj S. Dhadda, Michael J. Tisdale

Research output: Contribution to journalArticle

Abstract

Treatment of murine myotubes with high glucose concentrations (10 and 25 mM) stimulated protein degradation through the ubiquitin–proteasome pathway, and also caused activation (autophosphorylation) of PKR (double-stranded-RNA-dependent protein kinase) and eIF2a (eukaryotic initiation factor 2a). Phosphorylation of PKR and eIF2a was also seen in the gastrocnemius muscle of diabetic ob/ob mice. High glucose levels also inhibited protein synthesis. The effect of glucose on protein synthesis and degradation was not seen in myotubes transfected with a catalytically inactive variant (PKR?6). High glucose also induced an increased activity of both caspase-3 and -8, which led to activation of PKR, since this was completely attenuated by the specific caspase inhibitors. Activation of PKR also led to activation of p38MAPK (mitogen activated protein kinase), leading to ROS (reactive oxygen species) formation, since this was attenuated by the specific p38MAPK inhibitor SB203580. ROS formation was important in protein degradation, since it was completely attenuated by the antioxidant butylated hydroxytoluene. These results suggest that high glucose induces muscle atrophy through the caspase-3/-8 induced activation of PKR, leading to phosphorylation of eIF2a and depression of protein synthesis, together with PKR-mediated ROS production, through p38MAPK and increased protein degradation.
LanguageEnglish
Pages16-25
Number of pages10
JournalExperimental Cell Research
Volume315
Issue number1
DOIs
Publication statusPublished - 1 Jan 2009

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Muscle Proteins
Hyperglycemia
Eukaryotic Initiation Factors
Proteolysis
Glucose
Reactive Oxygen Species
Caspase 8
Skeletal Muscle Fibers
Caspase 3
Phosphorylation
eIF-2 Kinase
Butylated Hydroxytoluene
Caspase Inhibitors
Muscular Atrophy
Double-Stranded RNA
Proteasome Endopeptidase Complex
Ubiquitin
Mitogen-Activated Protein Kinases
Skeletal Muscle
Proteins

Keywords

  • caspase-3/-8
  • double-stranded-RNA-dependent protein kinase (PKR)
  • eukaryotic initiation factor 2α
  • eIF2α
  • p38 mitogen activated protein kinase
  • p38MAPK
  • reactive oxygen species activated protein kinase
  • reactive oxygen species

Cite this

Russell, Steve T. ; Rajani, Seema ; Dhadda, Raj S. ; Tisdale, Michael J. / Mechanism of induction of muscle protein loss by hyperglycaemia. In: Experimental Cell Research. 2009 ; Vol. 315, No. 1. pp. 16-25.
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Mechanism of induction of muscle protein loss by hyperglycaemia. / Russell, Steve T.; Rajani, Seema; Dhadda, Raj S.; Tisdale, Michael J.

In: Experimental Cell Research, Vol. 315, No. 1, 01.01.2009, p. 16-25.

Research output: Contribution to journalArticle

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