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

Abstract

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 microg x kg(-1) x day(-1)) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 microU/ml), 2) fed control (25 microU/ml), and 3) fed pST-treated (50 microU/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.

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

“…This is consistent with previous data in neonatal pigs where increasing either insulin or amino acids independently increased rates of muscle protein synthesis to levels associated with feeding, whereas increasing both insulin and amino acids to fed levels showed no additional stimulation (12). In a recent study (52), we demonstrated using pancreatic-glucose-amino acid clamps that rates of muscle protein synthesis were not further increased by raising circulating concentrations of insulin from fed untreated levels (25 U/ml) to plasma insulin levels seen in fed pST-treated animals (50 U/ml) when pigs are treated with pST (52). Taken together, it appears that the pST-induced increase in circulating insulin concentrations does not mediate the pST-induced increase in muscle protein synthesis, but fed amino acids are required for the pST-induced increase in muscle protein synthesis.…”

“…Although the increase in circulating glucose and insulin levels with pST treatment has been attributed to insulin resistance (28,53), kinetic studies indicate that reduced insulin-stimulated glucose uptake occurs in adipose tissue, not skeletal muscle (17,53). Even though insulin is known to promote skeletal muscle protein synthesis in a dose-dependent manner (38), we have demonstrated, by using pancreatic-glucose-aminoacid clamps, that the pST-induced increase in muscle protein synthesis is not due to the pST-induced increase in insulin concentration (52). We postulated that the inability of increased circulating insulin levels to further enhance rates of protein synthesis in the skeletal muscle of pST-treated pigs might be a consequence of the limited amino acid supply induced by maintaining amino acids at fasting concentrations.…”

“…Compared with diluent-treated animals, pigs treated with pST have higher circulating postparandial insulin levels (17), an independent promoter of protein synthesis in the growing animal (12,39). However, increased circulating insulin concentrations alone does not account for the pST-induced increase in protein synthesis (52). This study aimed to determine whether increased insulin concentrations in the presence of fed amino acid levels were required for the associated enhancement of skeletal muscle protein synthesis following pST treatment.…”

Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) and serine biosynthetic pathway genes are co-ordinately increased during anabolic agent-induced skeletal muscle growth

“…Research using animal models has robustly demonstrated that GH administration increases net protein accretion in skeletal muscle by increasing protein synthesis 5 6 14 15 . GH administration stimulates endogenous production of insulin-like growth factor 1 (IGF-1; predominantly in the liver), which is considered at least partly accountable for the anabolic effects of GH 16 17 18 .…”