Modulation of skeletal muscle protein synthesis by amino acids and insulin during sepsis

Jurasinski, C. V.; Gray, Kathleen; Vary, Thomas C.

doi:10.1016/0026-0495(95)90005-5

Cited by 51 publications

(75 citation statements)

References 36 publications

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“…For example, in sepsis, skeletal muscle protein synthesis is suppressed, and these cells are resistant to the stimulation of protein synthesis by insulin or amino acids (21). Consistent with these observations, eIF2B⑀ has been reported to be hyperphosphorylated in sepsis (19), and this hyperphosphorylation can be ameliorated with administration of TNF-␣-binding protein (19).…”

Section: Discussionsupporting

confidence: 71%

Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis

Kimball¹,

O'Malley²,

Anthony³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis. Am J Physiol Endocrinol Metab 287: E772-E780, 2004. First published June 8, 2004 10.1152/ajpendo.00535.2003.-Loss of muscle strength is a principal factor in the development of physical frailty, a condition clinically associated with increased risk of bone fractures, impairments in the activities of daily living, and loss of independence in older humans. A primary determinant in the decline in muscle strength that occurs during aging is a loss of muscle mass, which could occur through a reduction in the rate of protein synthesis, an elevation in protein degradation, or a combination of both. In the present study, rates of protein synthesis and the relative expression and function of various biomarkers involved in the initiation of mRNA translation in skeletal muscle were examined at different times throughout the life span of the rat. It was found that between 1 and 6 mo of age, body weight increased fourfold. However, by 6 mo, gastrocnemius protein synthesis and RNA content per gram of muscle were lower than values observed in 1-mo-old rats. Moreover, the relative expression of two proteins involved in the binding of initiator methionyl-tRNA to the 40S ribosomal subunit, eukaryotic initiation factors (eIF)2 and eIF2B, as well as the 70-kDa ribosomal protein S6 kinase, S6K1, was lower at 6 mo compared with 1 mo of age. Muscle mass, protein synthesis, and the aforementioned biomarkers remained unchanged until ϳ21 mo. Between 21 and 24 mo of age, muscle mass decreased precipitously. Surprisingly, during this period protein synthesis, relative RNA content, eIF2B activity, relative eIF2 expression, and S6K1 phosphorylation all increased. The results are consistent with a model wherein protein synthesis is enhanced during aging in a futile attempt to maintain muscle mass. translation initiation; eukaryotic initiation factor; ribosomal protein S6 kinase; aging SARCOPENIA, the disproportionate loss of skeletal muscle that occurs during the last quartile of the life span, has been well documented in many species, including humans (4, 33). A number of physiological factors have been suggested to be involved in sarcopenia, including an age-related reduction of hormones such as growth hormone (22), thyroxine (30), and, in women and men, estrogen and testosterone (29), respectively.

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Section: Discussionsupporting

confidence: 71%

Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis

Kimball¹,

O'Malley²,

Anthony³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…This contrasts with the observed insulin resistance for AA metabolism in an adult rat model of sepsis (45). The high sensitivity to insulin in the neonatal muscle (18,20,22), and an apparent lack of development of insulin resistance during prolonged endotoxemia in the neonate, likely contribute to the lower serum BCAA levels in the LPS group.…”

mentioning

confidence: 70%

“…Because insulin resistance has been implicated in the reduction in protein synthesis in different adult models of sepsis (26,45), we speculate that the fact that muscle protein synthesis was only modestly reduced in this neonatal model of endotoxemia may be ascribed to the unique sensitivity and responsiveness of neonatal muscle protein synthesis to insulin and amino acids. Because of the endogenous production of insulin induced by glucose and amino acid infusion, the enhanced sensitivity of neonatal muscle protein synthesis to these anabolic agents (17,18,20,22), and the lack of apparent insulin resistance in this model, it appears that the elevation in insulin and/or amino acids to fed levels (18,22,27) may have circumvented some of the catabolic effects induced by the septic-like state (15) and blunted the reduction in muscle protein synthesis by endotoxin.…”

mentioning

confidence: 89%

Regulation of Muscle Protein Synthesis in Neonatal Pigs During Prolonged Endotoxemia

et al. 2004

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“…Amino acid refeeding after short-term starvation increases muscle protein synthesis, and physiologically-relevant concentrations of amino acids enhance synthesis in the perfused hindlimb, in incubated muscle, and cultured myocytes (2)(3)(4)(5)(6)(7)(8). The branched-chain amino acid leucine accounts for all or most of the ability of a mixture of amino acids to stimulate protein synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…The branched-chain amino acid leucine accounts for all or most of the ability of a mixture of amino acids to stimulate protein synthesis. Moreover, the anabolic effects of leucine are mediated by cell signaling pathways which stimulate translation initiation via activation of mammalian target of rapamycin (mTOR) (2)(3)(4)(5)(6)(7)(8)(9)(10). This protein kinase represents a point of signal amplification because stimulation of mTOR phosphorylates multiple substrates which enhance translation, including eukaryotic initiation factor 4E-binding protein (4E-BP1) and the ribosomal protein (rp) S6 kinase-1(S6K1) (11).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

Lang

Frost

2006

Mol Med

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Sepsis blunts the ability of nutrient signaling by leucine to stimulate skeletal muscle protein synthesis by impairing translation initiation. The present study tested the hypothesis that overproduction of either tumor necrosis factor (TNF)-α or glucocorticoids mediate the sepsis-induced leucine resistance. Prior to producing peritonitis, rats received either vehicle, TNF binding protein (TNF BP ) to inhibit endogenous TNFα action, and/or the glucocorticoid receptor antagonist RU486. Leucine was orally administered to all rats 24 h thereafter and the gastrocnemius removed 20 min later to assess protein synthesis and signaling components important in controlling peptide-chain initiation. Muscle protein synthesis was 65% lower in septic rats administered leucine than in leucinetreated control animals. This reduction was not prevented by either TNF BP or RU486 alone, but was completely reversed by the combination. This sepsis-induced leucine resistance was associated with an 80% reduction in the amount of active eIF4E·eIF4G complex, a 5-fold increase in the formation of the inactive eIF4E·4E-BP1 complex as well as markedly reduced (at least 70%) phosphorylation of 4E-BP1, eIF4G, S6K1, S6, and mTOR. Pretreatment of septic rats with either TNF BP or RU486 individually only nominally improved the leucine action as assessed by the above-mentioned endpoints. In contrast, when TNF BP and RU486 were co-administered, the ability of sepsis to impair the leucine-stimulated phosphorylation of 4E-BP1, eIF4G, S6K1, and S6 as well as the redistribution of eIF4E was essentially prevented. No differences in the total amount or phosphorylation of eIF2α and eIF2Bε were detected between the different groups, and changes could not be attributed to differences in the prevailing plasma concentration of insulin or leucine. Our data demonstrate the sepsis-induced leucine resistance in skeletal muscle results from the cooperative interaction of both TNFα and glucocorticoids.

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Modulation of skeletal muscle protein synthesis by amino acids and insulin during sepsis

Cited by 51 publications

References 36 publications

Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis

Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis

Regulation of Muscle Protein Synthesis in Neonatal Pigs During Prolonged Endotoxemia

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

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