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Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
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Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice

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Protein breakdown in muscle from burned rats is blocked by insulin-like growth factor i and glycogen synthase

Cheng-Hui Fang1, Bing-Guo Li, J Howard James

  • 1Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, Ohio 45229, USA. cfang@shrinenet.org

Endocrinology
|April 2, 2005
PubMed

Insights

Insulin-like growth factor-I (IGF-I) inhibits muscle protein breakdown via a phosphotidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3beta (GSK-3beta) pathway. This mechanism is crucial for IGF-I

Area of Science:

  • Muscle physiology
  • Molecular signaling
  • Biochemistry

Background:

  • Insulin-like growth factor-I (IGF-I) is known to inhibit burn-induced muscle proteolysis.
  • The phosphotidylinositol 3-kinase (PI3K)/Akt pathway and Forkhead box O transcription factors are implicated in IGF-I's anabolic effects.
  • Other signaling pathways involved in IGF-I's anticatabolic effects remain less understood.

Purpose of the Study:

  • To investigate the roles of mammalian target of rapamycin (mTOR), glycogen synthase kinase-3beta (GSK-3beta) phosphorylation, MAPK, and calcineurin signaling pathways in IGF-I's anticatabolic effects.
  • To elucidate the specific mechanisms by which IGF-I inhibits muscle proteolysis.

Main Methods:

  • Incubation of extensor digitorum longus muscles from burned rats with IGF-I and specific signaling pathway inhibitors.
  • Assessment of protein breakdown and phosphorylation of key signaling molecules.
  • Utilized PI3K inhibitors (LY294002, wortmannin), GSK-3beta inhibitors (lithium chloride, thiadiazolidinone-8), and inhibitors of mTOR, MAPK, and calcineurin.

Main Results:

  • PI3K inhibitors reduced basal protein breakdown; IGF-I showed no additional inhibition.
  • IGF-I-induced inhibition of proteolysis correlated with GSK-3beta phosphorylation (inactivation).
  • GSK-3beta inhibitors mimicked IGF-I's effect on reducing protein breakdown; mTOR, MAPK, and calcineurin pathways were not involved.

Conclusions:

  • IGF-I inhibits muscle protein breakdown, at least partly, through a PI3K/Akt/GSK-3beta-dependent mechanism.
  • Similar mechanisms were observed in muscles from nonburned rats.
  • IGF-I employs multiple pathways, including PI3K/Akt-mediated GSK-3beta and Foxo transcription factor inactivation, to inhibit skeletal muscle protein breakdown.

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