scholarly journals Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin

2008 ◽  
Vol 295 (1) ◽  
pp. E187-E194 ◽  
Author(s):  
Fiona A. Wilson ◽  
Renán A. Orellana ◽  
Agus Suryawan ◽  
Hanh V. Nguyen ◽  
Asumthia S. Jeyapalan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Growing Pigs ◽  
Initiation Factor ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Stimulation Of

Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7–10 days of pST (150 μg·kg−1·day−1) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 μU/ml), 2) fed control (25 μU/ml), and 3) fed pST-treated (50 μU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1·eIF4E complex association and increased active eIF4E·eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation.

Developmental changes in the feeding-induced stimulation of translation initiation in muscle of neonatal pigs

2000 ◽  
Vol 279 (6) ◽  
pp. E1226-E1234 ◽  
Author(s):  
Teresa A. Davis ◽  
Hanh V. Nguyen ◽  
Agus Suryawan ◽  
Jill A. Bush ◽  
Leonard S. Jefferson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Developmental Changes ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Hyperphosphorylated Form ◽  
Stimulation Of

The rapid gain in skeletal muscle mass in the neonate is associated with a marked elevation in skeletal muscle protein synthesis in response to feeding. The feeding-induced response decreases with development. To determine whether the response to feeding is regulated at the level of translation initiation, the expression, phosphorylation, and function of a number of eukaryotic initiation factors (eIF) were examined. Pigs at 7 and 26 days of age were either fasted overnight or fed porcine milk after an overnight fast. In muscle of 7-day-old pigs, the hyperphosphorylated form of the eIF4E repressor protein, 4E-binding protein 1 (4E-BP1), was undetectable in the fasting state but rose to 60% of total 4E-BP1 after feeding; eIF4E phosphorylation was unaffected by feeding status. The amount of eIF4E in the inactive 4E-BP1 · eIF4E complex was reduced by 80%, and the amount of eIF4E in the active eIF4E · eIF4G complex was increased 14-fold in muscle of 7-day-old pigs after feeding. The amount of 70-kDa ribosomal protein S6 (p70S6) kinase in the hyperphosphorylated form rose 2.5-fold in muscle of 7-day-old pigs after feeding. Each of these feeding-induced responses was blunted in muscle of 26-day-old pigs. eIF2B activity in muscle was unaffected by feeding status but decreased with development. Feeding produced similar changes in eIF characteristics in liver and muscle; however, the developmental changes in liver were not as apparent as in skeletal muscle. Thus the results demonstrate that the developmental change in the acute stimulation of skeletal muscle protein synthesis by feeding is regulated by the availability of eIF4E for 48S ribosomal complex formation. The results further suggest that the overall developmental decline in skeletal muscle protein synthesis involves regulation by eIF2B.

scholarly journals BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice

2010 ◽  
Vol 299 (3) ◽  
pp. R935-R944 ◽  
Author(s):  
Charles H. Lang ◽  
Christopher J. Lynch ◽  
Thomas C. Vary
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Protein Interactions ◽  
Knockout Mice ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Initiation Factor ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Branched Chain

Endotoxin (LPS) and sepsis decrease mammalian target of rapamycin (mTOR) activity in skeletal muscle, thereby reducing protein synthesis. Our study tests the hypothesis that inhibition of branched-chain amino acid (BCAA) catabolism, which elevates circulating BCAA and stimulates mTOR, will blunt the LPS-induced decrease in muscle protein synthesis. Wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout mice were studied 4 h after Escherichia coli LPS or saline. Basal skeletal muscle protein synthesis was increased in knockout mice compared with WT, and this change was associated with increased eukaryotic initiation factor (eIF)-4E binding protein-1 (4E-BP1) phosphorylation, eIF4E·eIF4G binding, 4E-BP1·raptor binding, and eIF3·raptor binding without a change in the mTOR·raptor complex in muscle. LPS decreased muscle protein synthesis in WT mice, a change associated with decreased 4E-BP1 phosphorylation as well as decreased formation of eIF4E·eIF4G, 4E-BP1·raptor, and eIF3·raptor complexes. In BCATm knockout mice given LPS, muscle protein synthesis only decreased to values found in vehicle-treated WT control mice, and this ameliorated LPS effect was associated with a coordinate increase in 4E-BP1·raptor, eIF3·raptor, and 4E-BP1 phosphorylation. Additionally, the LPS-induced increase in muscle cytokines was blunted in BCATm knockout mice, compared with WT animals. In a separate study, 7-day survival and muscle mass were increased in BCATm knockout vs. WT mice after polymicrobial peritonitis. These data suggest that elevating blood BCAA is sufficient to ameliorate the catabolic effect of LPS on skeletal muscle protein synthesis via alterations in protein-protein interactions within mTOR complex-1, and this may provide a survival advantage in response to bacterial infection.

scholarly journals Fed levels of amino acids are required for the somatotropin-induced increase in muscle protein synthesis

2008 ◽  
Vol 295 (4) ◽  
pp. E876-E883 ◽  
Author(s):  
Fiona A. Wilson ◽  
Agus Suryawan ◽  
Renán A. Orellana ◽  
Hanh V. Nguyen ◽  
Asumthia S. Jeyapalan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Growing Pigs ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Skeletal Muscle Protein

Chronic somatotropin (pST) treatment in pigs increases muscle protein synthesis and circulating insulin, a known promoter of protein synthesis. Previously, we showed that the pST-mediated rise in insulin could not account for the pST-induced increase in muscle protein synthesis when amino acids were maintained at fasting levels. This study aimed to determine whether the pST-induced increase in insulin promotes skeletal muscle protein synthesis when amino acids are provided at fed levels and whether the response is associated with enhanced translation initiation factor activation. Growing pigs were treated with pST (0 or 180 μg·kg−1·day−1) for 7 days, and then pancreatic-glucose-amino acid clamps were performed. Amino acids were raised to fed levels in the presence of either fasted or fed insulin concentrations; glucose was maintained at fasting throughout. Muscle protein synthesis was increased by pST treatment and by amino acids (with or without insulin) ( P < 0.001). In pST-treated pigs, fed, but not fasting, amino acid concentrations further increased muscle protein synthesis rates irrespective of insulin level ( P < 0.02). Fed amino acids, with or without raised insulin concentrations, increased the phosphorylation of S6 kinase (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4EBP1), decreased inactive 4EBP1·eIF4E complex association, and increased active eIF4E·eIF4G complex formation ( P < 0.02). pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of muscle protein synthesis requires fed amino acid levels, but not fed insulin levels. However, under the current conditions, the response to amino acids is not mediated by the activation of translation initiation factors that regulate mRNA binding to the ribosomal complex.

Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigs

2006 ◽  
Vol 291 (4) ◽  
pp. E849-E859 ◽  
Author(s):  
Agus Suryawan ◽  
Jeffery Escobar ◽  
Jason W. Frank ◽  
Hanh V. Nguyen ◽  
Teresa A. Davis
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Growth Factor ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Developmental Regulation ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Signaling Components

The rapid growth of neonates is driven by high rates of skeletal muscle protein synthesis. This high rate of protein synthesis, which is induced by feeding, declines with development. Overnight-fasted 7- and 26-day-old pigs either remained fasted or were refed, and the abundance and phosphorylation of growth factor- and nutrient-induced signaling components that regulate mRNA translation initiation were measured in skeletal muscle and liver. In muscle, but not liver, the activation of inhibitors of protein synthesis, phosphatase and tensin homolog deleted on chromosome 10, protein phosphatase 2A, and tuberous sclerosis complex 1/2 increased with age. Serine/threonine phosphorylation of the insulin receptor and insulin receptor substrate-1, which downregulates insulin signaling, and the activation of AMP-activated protein kinase, an inhibitor of protein synthesis, were unaffected by age and feeding in muscle and liver. Activation of positive regulators of protein synthesis, mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), and eIF4E-binding protein-1 (4E-BP1) decreased with age in muscle but not liver. Feeding enhanced mTOR, S6K1, and 4E-BP1 activation in muscle, and this response decreased with age. In liver, activation of S6K1 and 4E-BP1, but not mTOR, was increased by feeding but was unaffected by age. Raptor abundance and the association between raptor and mTOR were greater in 7- than in 26-day-old pigs. The results suggest that the developmental decline in skeletal muscle protein synthesis is due in part to developmental regulation of the activation of growth factor and nutrient-signaling components.

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