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. 2016 Jun 1;310(11):E1072-84.
doi: 10.1152/ajpendo.00520.2015. Epub 2016 May 3.

Enteral β-hydroxy-β-methylbutyrate supplementation increases protein synthesis in skeletal muscle of neonatal pigs

Michelle Kao  1 , Daniel A Columbus  1 , Agus Suryawan  1 , Julia Steinhoff-Wagner  1 , Adriana Hernandez-Garcia  1 , Hanh V Nguyen  1 , Marta L Fiorotto  1 , Teresa A Davis  2
Affiliations

Enteral β-hydroxy-β-methylbutyrate supplementation increases protein synthesis in skeletal muscle of neonatal pigs

Michelle Kao et al. Am J Physiol Endocrinol Metab. .

Abstract

Many low-birth weight infants are at risk for poor growth due to an inability to achieve adequate protein intake. Administration of the amino acid leucine stimulates protein synthesis in skeletal muscle of neonates. To determine the effects of enteral supplementation of the leucine metabolite β-hydroxy-β-methylbutyrate (HMB) on protein synthesis and the regulation of translation initiation and degradation pathways, overnight-fasted neonatal pigs were studied immediately (F) or fed one of five diets for 24 h: low-protein (LP), high-protein (HP), or LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol HMB·kg body wt(-1)·day(-1) Cell replication was assessed from nuclear incorporation of BrdU in the longissimus dorsi (LD) muscle and jejunum crypt cells. Protein synthesis rates in LD, gastrocnemius, rhomboideus, and diaphragm muscles, lung, and brain were greater in HMB80 and HP and in brain were greater in HMB40 compared with LP and F groups. Formation of the eIF4E·eIF4G complex and S6K1 and 4E-BP1 phosphorylation in LD, gastrocnemius, and rhomboideus muscles were greater in HMB80 and HP than in LP and F groups. Phosphorylation of eIF2α and eEF2 and expression of SNAT2, LAT1, MuRF1, atrogin-1, and LC3-II were unchanged. Numbers of BrdU-positive myonuclei in the LD were greater in HMB80 and HP than in the LP and F groups; there were no differences in jejunum. The results suggest that enteral supplementation with HMB increases skeletal muscle protein anabolism in neonates by stimulation of protein synthesis and satellite cell proliferation.

Keywords: amino acid; infant; protein metabolism; translation initiation.

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Figures

Fig. 1.
Fig. 1.
Plasma β-hydroxy-β-methylbutyrate (HMB) concentrations in piglets fasted overnight and then fed low-protein diets supplemented with 2 (LP + HMB2), 20 (LP + HMB20), or 40 (LP + HMB40) μmol/kg body wt HMB or water with 40 μmol/kg HMB (H2O + HMB40). Values are means ± SE; n = 3–4.
Fig. 2.
Fig. 2.
Plasma HMB concentrations in piglets fasted overnight (F) or fed a low-protein diet (LP), LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol·kg−1·day−1 HMB for 24 h, or high-protein diet (HP). Values are means ± SE; n = 7–9. Time is given as hours from initiation of supplementation.
Fig. 3.
Fig. 3.
Fractional rates of protein synthesis in longissimus dorsi (A), gastrocnemius (B), soleus (C), rhomboideus (D), diaphragm (E), and heart (F) muscles of piglets that were fasted overnight (F) or fed a low-protein diet (LP), LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol·kg−1·day−1 HMB for 24 h, or high-protein diet (HP). Values are means ± SE; n = 7–9. a,b,c,d,eValues not sharing lowercase letters differ significantly, P < 0.05.
Fig. 4.
Fig. 4.
Fractional rates of protein synthesis in duodenum (A), jejunum (B), ileum (C), and colon (D) of piglets that were fasted overnight (F) or fed a low-protein diet (LP), LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol·kg−1·day−1 HMB for 24 h, or high-protein diet (HP). Values are means ± SE; n = 7–9. a,b,cValues not sharing lowercase letters differ significantly, P < 0.05.
Fig. 5.
Fig. 5.
Fractional rates of protein synthesis in stomach (A), liver (B), pancreas (C), spleen (D), kidney (E) skin, brain (G), and lung (H) of piglets that were fasted overnight (F) or fed a low-protein diet (LP), LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol·kg−1·day−1 HMB for 24 h, or high-protein diet (HP). Values are means ± SE; n = 7–9. a,b,cValues not sharing lowercase letters differ significantly, P < 0.05.
Fig. 6.
Fig. 6.
Abundance of eukaryotic initiation factor (eIF)4G·eIF4E in longissimus dorsi (A), gastrocnemius (B), soleus (C), rhomboideus (D), diaphragm (E), and heart (F) muscles of piglets that were fasted overnight (F) or fed a low-protein diet (LP), LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol·kg−1·day−1 HMB for 24 h, or high-protein diet (HP). Black lines between bands indicate where images from the same blots were spliced to adjust sample order on the membrane for presentation. Values are means ± SE; n = 7–9. a,b,c,d,eValues not sharing lowercase letters differ significantly, P < 0.05. AU, arbitrary units.
Fig. 7.
Fig. 7.
No. of 5-bromo-2′-deoxyuridine (BrdU) + myonuclei per fiber cross-section in longissimus dorsi muscles of piglets fed a low-protein diet (LP), LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol·kg−1·day−1 HMB for 24 h, or high-protein diet (HP). Values are means ± SE; n = 7–9. a,b,c,dValues not sharing lowercase letters differ significantly, P < 0.05.
Fig. 8.
Fig. 8.
Average no. of epithelial cells per crypt longitudinal section and the proportion of epithelial cells within a crypt section that were BrdU positive in the jejunum of piglets that were fed a low-protein diet (LP), LP diet supplemented with 80 μmol·kg−1·day−1 HMB for 24 h (HMB80), or high-protein diet (HP). Values are means ± SE; n = 7–9.
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