Local insulin-like growth factor I prevents sepsis-induced muscle atrophy

Gerald Nystrom, Anne Pruznak, Danuta Huber, Robert A. Frost, Charles H. Lang

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The present study tests the hypotheses that local bioavailability of insulin-like growth factor I (IGF-I) is capable of regulating muscle protein balance and that muscle-directed IGF-I can selectively maintain muscle mass during bacterial infection. Initial studies in C57BL/6 mice demonstrated that increasing or decreasing bioavailable IGF-I within muscle by local administration of either Leu24 Ala31 IGF-I or IGF binding protein 1, respectively, produced proportional changes in surrogate markers (eg, phosphorylation of 4E-BP1 and S6K1) of protein synthesis. We next examined the ability of a sustained local administration of IGF-I to prevent sepsis-induced muscle atrophy over a 5-day period. At the time of cecal ligation and puncture or sham surgery, mice had a time-release pellet containing IGF-I implanted next to the gastrocnemius and a placebo pellet placed in the contralateral limb. Data indicated that IGF-I released locally only affected the adjacent muscle and was not released into the circulation. Gastrocnemius from septic mice containing the placebo pellet was atrophied and had a reduced IGF-I protein content. In contrast, locally directed IGF-I increased IGF-I protein within adjacent muscle to basal control levels. This change was associated with a proportional increase in muscle weight and protein, as well as increased phosphorylation of 4E-BP1 and the redistribution of eIF4E from the inactive eIF4E{bullet operator}4EBP1 complex to the active eIF4E{bullet operator}eIF4G complex. Local IGF-I also prevented the sepsis-induced increase in atrogin-1 messenger RNA in the exposed muscle. Finally, local IGF-I prevented the sepsis-induced increase in muscle interleukin-6 messenger RNA. Thus, muscle-directed IGF-I attenuates the sepsis-induced atrophic response apparently by increasing muscle protein synthesis and potentially decreasing proteolysis. Collectively, our data suggest that agents that increase the bioavailability of IGF-I within muscle per se might be effective in ameliorating the sepsis-induced loss of muscle mass without having undesirable effects on metabolic processes in distant organs.

Original languageEnglish (US)
Pages (from-to)787-797
Number of pages11
JournalMetabolism: Clinical and Experimental
Volume58
Issue number6
DOIs
StatePublished - Jun 1 2009

Fingerprint

Muscular Atrophy
Insulin-Like Growth Factor I
Sepsis
Muscles
Muscle Proteins
Insulin-Like Growth Factor Binding Protein 1
Biological Availability
Placebos
Phosphorylation
Messenger RNA
Proteins
Inbred C57BL Mouse
Punctures
Bacterial Infections
Proteolysis
Ligation
Interleukin-6

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Nystrom, Gerald ; Pruznak, Anne ; Huber, Danuta ; Frost, Robert A. ; Lang, Charles H. / Local insulin-like growth factor I prevents sepsis-induced muscle atrophy. In: Metabolism: Clinical and Experimental. 2009 ; Vol. 58, No. 6. pp. 787-797.
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Local insulin-like growth factor I prevents sepsis-induced muscle atrophy. / Nystrom, Gerald; Pruznak, Anne; Huber, Danuta; Frost, Robert A.; Lang, Charles H.

In: Metabolism: Clinical and Experimental, Vol. 58, No. 6, 01.06.2009, p. 787-797.

Research output: Contribution to journalArticle

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AU - Nystrom, Gerald

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AB - The present study tests the hypotheses that local bioavailability of insulin-like growth factor I (IGF-I) is capable of regulating muscle protein balance and that muscle-directed IGF-I can selectively maintain muscle mass during bacterial infection. Initial studies in C57BL/6 mice demonstrated that increasing or decreasing bioavailable IGF-I within muscle by local administration of either Leu24 Ala31 IGF-I or IGF binding protein 1, respectively, produced proportional changes in surrogate markers (eg, phosphorylation of 4E-BP1 and S6K1) of protein synthesis. We next examined the ability of a sustained local administration of IGF-I to prevent sepsis-induced muscle atrophy over a 5-day period. At the time of cecal ligation and puncture or sham surgery, mice had a time-release pellet containing IGF-I implanted next to the gastrocnemius and a placebo pellet placed in the contralateral limb. Data indicated that IGF-I released locally only affected the adjacent muscle and was not released into the circulation. Gastrocnemius from septic mice containing the placebo pellet was atrophied and had a reduced IGF-I protein content. In contrast, locally directed IGF-I increased IGF-I protein within adjacent muscle to basal control levels. This change was associated with a proportional increase in muscle weight and protein, as well as increased phosphorylation of 4E-BP1 and the redistribution of eIF4E from the inactive eIF4E{bullet operator}4EBP1 complex to the active eIF4E{bullet operator}eIF4G complex. Local IGF-I also prevented the sepsis-induced increase in atrogin-1 messenger RNA in the exposed muscle. Finally, local IGF-I prevented the sepsis-induced increase in muscle interleukin-6 messenger RNA. Thus, muscle-directed IGF-I attenuates the sepsis-induced atrophic response apparently by increasing muscle protein synthesis and potentially decreasing proteolysis. Collectively, our data suggest that agents that increase the bioavailability of IGF-I within muscle per se might be effective in ameliorating the sepsis-induced loss of muscle mass without having undesirable effects on metabolic processes in distant organs.

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