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Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs.

ABSTRACT: Acute infection promotes skeletal muscle wasting and insulin resistance, but the effect of insulin on energy and substrate sensing in skeletal muscle of chronically infected neonates has not been studied.Eighteen 2-d-old pigs underwent cecal ligation and puncture (CLP) or sham surgery (CON) to induce a chronic infection for 5 d. On d 5, pancreatic-substrate clamps were performed to attain fasting or fed insulin levels but to maintain glucose and amino acids in the fasting range. Total fractional protein synthesis rates (Ks), translational control mechanisms, and energy sensing and degradation signal activation were measured in longissimus dorsi muscle.In fasting conditions, CLP reduced Ks and sirtuin 1 (SIRT1) and increased AMP-activated protein kinase ? (AMPK?) activation and muscle RING-finger protein-1 (MuRF1). Insulin treatment increased Ks and mitochondrial protein synthesis, enhanced translation activation, and reduced SIRT1 in CON. In contrast, in CLP, insulin treatment increased Ks, protein kinase B (PKB) and Forkhead box O1 phosphorylation, antagonized AMPK activation, and decreased peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC-1?), MuRF1, and SIRT1.Energy and substrate sensing in skeletal muscle by the PKB-AMPK-SIRT1-PGC-1? axis is impacted by chronic infection in neonatal pigs and can be modulated by insulin.

SUBMITTER: Manjarin R

PROVIDER: S-EPMC5746053 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs.

Manjarín Rodrigo R Suryawan Agus A Koo Sue J SJ Wilson Fiona A FA Nguyen Hanh V HV Davis Teresa A TA Orellana Renán A RA

Pediatric research 20160620 5

<h4>Background</h4>Acute infection promotes skeletal muscle wasting and insulin resistance, but the effect of insulin on energy and substrate sensing in skeletal muscle of chronically infected neonates has not been studied.<h4>Methods</h4>Eighteen 2-d-old pigs underwent cecal ligation and puncture (CLP) or sham surgery (CON) to induce a chronic infection for 5 d. On d 5, pancreatic-substrate clamps were performed to attain fasting or fed insulin levels but to maintain glucose and amino acids in ...[more]

PMID: 27508897

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Project description:BackgroundNutrition administered as intermittent bolus feeds rather than continuously promotes greater protein synthesis rates in skeletal muscle and enhances lean growth in a neonatal piglet model. The molecular mechanisms responsible remain unclear.ObjectivesWe aimed to identify the insulin- and/or amino acid-signaling components involved in the enhanced stimulation of skeletal muscle by intermittent bolus compared to continuous feeding in neonatal pigs born at term.MethodsTerm piglets (2-3 days old) were fed equal amounts of sow milk replacer [12.8 g protein and 155 kcal/(kg body weight · d)] by orogastric tube as intermittent bolus meals every 4 hours (INT) or by continuous infusion (CTS). After 21 days, gastrocnemius muscle samples were collected from CTS, INT-0 (before a meal), and INT-60 (60 minutes after a meal) groups (n = 6/group). Insulin- and amino acid-signaling components relevant to mechanistic target of rapamycin complex (mTORC) 1 activation and protein translation were measured.ResultsPhosphorylation of the insulin receptor, IRS-1, PDK1, mTORC2, pan-Akt, Akt1, Akt2, and TSC2 was 106% to 273% higher in the skeletal muscle of INT-60 piglets than in INT-0 and CTS piglets (P < 0.05), but phosphorylation of PTEN, PP2A, Akt3, ERK1/2, and AMPK did not differ among groups, nor did abundances of PHLPP, SHIP2, and Ubl4A. The association of GATOR2 with Sestrin1/2, but not CASTOR1, was 51% to 52% lower in INT-60 piglets than in INT-0 and CTS piglets (P < 0.05), but the abundances of SLC7A5/LAT1, SLC38A2/SNAT2, SLC38A9, Lamtor1/2, and V-ATPase did not differ. Associations of mTOR with RagA, RagC, and Rheb and phosphorylation of S6K1 and 4EBP1, but not eIF2α and eEF2, were 101% to 176% higher in INT-60 piglets than in INT-0 and CTS piglets (P < 0.05).ConclusionsThe enhanced rates of muscle protein synthesis and growth with intermittent bolus compared to continuous feeding in a neonatal piglet model can be explained by enhanced activation of both the insulin- and amino acid-signaling pathways that regulate translation initiation.

Project description:BackgroundPostnatal growth failure in premature infants is associated with reduced lean mass accretion. Prematurity impairs the feeding-induced stimulation of translation initiation and protein synthesis in the skeletal muscle of neonatal pigs. The objective was to determine whether body weight independently contributes to the blunted postprandial protein synthesis.MethodsPreterm and term pigs that were either fasted or fed were stratified into quartiles according to birth weight to yield preterm and term groups of similar body weight; first and second quartiles of preterm pigs and third and fourth quartiles of term pigs were compared (preterm-fasted, n = 23; preterm-fed, n = 25; term-fasted, n = 21; term-fed, n = 21). Protein synthesis rates and mechanistic target of rapamycin complex 1 (mTORC1) activation in skeletal muscle were determined.ResultsRelative body weight gain was lower in preterm compared to term pigs. Prematurity attenuated the feeding-induced increase in mTORC1 activation in longissimus dorsi and gastrocnemius muscles (P < 0.05). Protein synthesis in gastrocnemius (P < 0.01), but not in longissimus dorsi muscle, was blunted by preterm birth.ConclusionA lower capacity of skeletal muscle to respond adequately to feeding may contribute to reduced body weight gain and lean mass accretion in preterm infants.ImpactThis study has shown that the feeding-induced increase in protein synthesis of skeletal and cardiac muscle is blunted in neonatal pigs born preterm compared to pigs born at term independently of birth weight. These findings support the notion that preterm birth, and not low birth weight, impairs the capacity of skeletal and cardiac muscle to upregulate mechanistic target of rapamycin-dependent anabolic signaling pathways and protein synthesis in response to the postprandial increase in insulin and amino acids. These observations suggest that a blunted anabolic response to feeding contributes to reduced lean mass accretion and altered body composition in preterm infants.

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Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs.

Publications

Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs.

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