Gao Xuejin, Tian Feng, Wang Xinying, Zhao Jie, Wan Xiao, Zhang Li, Wu Chao, Li Ning, Li Jieshou
Research Institute of General Surgery, Jinling Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China.
PLoS One. 2015 Apr 24;10(4):e0125023. doi: 10.1371/journal.pone.0125023. eCollection 2015.
Protein-energy malnutrition (PEM) can lead to growth hormone (GH) resistance. Leucine supplementation diets have been shown to increase protein synthesis in muscles. Our study aimed at investigating if long-term leucine supplementation could modulate GH-insulin-like growth factor (IGF)-1 system function and mammalian target of rapamycin (mTOR)-related signal transduction in skeletal muscles in a rat model of severe malnutrition.
METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague-Dawley rats (n = 50; weight, 302 ± 5 g) were divided into 5 treatment groups, including 2 control groups (a normal control group that was fed chow and ad libitum water [CON, n = 10] and a malnourished control group [MC, n = 10] that was fed a 50% chow diet). After undergoing a weight loss stage for 4 weeks, rats received either the chow diet (MC-CON, n = 10), the chow diet supplemented with low-dose leucine (MC-L, n = 10), or the chow diet supplemented with high-dose leucine (MC-H, n = 10) for 2 weeks. The muscle masses of the gastrocnemius, soleus, and extensor digitorum longus were significantly reduced in the MC group. Re-feeding increased muscle mass, especially in the MC-L and MC-H groups. In the MC group, serum IGF-1, IGF-binding protein (IGFBP)-3, and hepatic growth hormone receptor (GHR) levels were significantly decreased and phosphorylation of the downstream anabolic signaling effectors protein kinase B (Akt), mTOR, and ribosomal protein S6 kinase 1 (S6K1) were significantly lower than in other groups. However, serum IGF-1 and IGF binding protein (IGFBP)-3 concentrations and hepatic growth hormone receptor (GHR) levels were significantly higher in the MC-L and MC-H groups than in the MC-CON group, and serum IGFBP-1 levels was significantly reduced in the MC-L and MC-H groups. These changes were consistent with those observed for hepatic mRNA expression levels. Phosphorylation of the downstream anabolic signaling effectors Akt, mTOR, and S6K1 were also significantly higher in the MC-L and MC-H groups than in the MC-CON group.
CONCLUSION/SIGNIFICANCE: Our data are the first to demonstrate that long-term supplementation with leucine improved acquired growth hormone resistance in rats with protein-energy malnutrition. Leucine might promote skeletal muscle protein synthesis by regulating downstream anabolic signaling transduction.
蛋白质能量营养不良（PEM）可导致生长激素（GH）抵抗。补充亮氨酸的饮食已被证明可增加肌肉中的蛋白质合成。我们的研究旨在调查在严重营养不良的大鼠模型中，长期补充亮氨酸是否能调节骨骼肌中GH-胰岛素样生长因子（IGF）-1系统功能以及雷帕霉素哺乳动物靶蛋白（mTOR）相关信号转导。
方法/主要发现：雄性斯普拉格-道利大鼠（n = 50；体重，302±5 g）分为5个治疗组，包括2个对照组（一个正常对照组，给予普通饲料并自由饮水[CON，n = 10]，一个营养不良对照组[MC，n = 10]，给予50%的普通饲料）。在经历4周的体重减轻阶段后，大鼠接受普通饲料（MC-CON，n = 10）、补充低剂量亮氨酸的普通饲料（MC-L，n = 10）或补充高剂量亮氨酸的普通饲料（MC-H，n = 10），持续2周。MC组腓肠肌、比目鱼肌和趾长伸肌的肌肉质量显著降低。重新喂食增加了肌肉质量，尤其是在MC-L组和MC-H组。在MC组中，血清IGF-1、IGF结合蛋白（IGFBP）-3和肝脏生长激素受体（GHR）水平显著降低，下游合成代谢信号效应蛋白激酶B（Akt）、mTOR和核糖体蛋白S6激酶1（S6K1）的磷酸化水平显著低于其他组。然而，MC-L组和MC-H组的血清IGF-1和IGF结合蛋白（IGFBP）-3浓度以及肝脏生长激素受体（GHR）水平显著高于MC-CON组，而MC-L组和MC-H组的血清IGFBP-1水平显著降低。这些变化与肝脏mRNA表达水平观察到的数据一致。MC-L组和MC-H组中，下游合成代谢信号效应蛋白Akt、mTOR和S6K1的磷酸化水平也显著高于MC-CON组。
结论/意义：我们的数据首次证明，长期补充亮氨酸可改善蛋白质能量营养不良大鼠获得性生长激素抵抗。亮氨酸可能通过调节下游合成代谢信号转导促进骨骼肌蛋白质合成。
