Guillet Christelle, Prod'homme Magali, Balage Michèle, Gachon Pierre, Giraudet Christophe, Morin Liliane, Grizard Jean, Boirie Yves
Unité du Métabolisme Protéino-Energétique, UMR Université d'Auvergne/INRA, CRNH, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
FASEB J. 2004 Oct;18(13):1586-7. doi: 10.1096/fj.03-1341fje. Epub 2004 Aug 19.
Age-related loss of muscle protein may involve a decreased response to anabolic factors of muscle protein synthesis through dysregulation of translation factors. To verify this hypothesis, we simultaneously investigated muscle protein synthesis and expression of some factors implicated in insulin signal transduction during hyperinsulinemia and hyperaminoacidemia in 6 young (25+/-1 year; mean+/-sem) and 8 elderly subjects (72+/-2 year). Incorporation of L-[1-13C] leucine in muscle proteins (fractional synthesis rate, FSR) was measured in vastus lateralis, before and during a euglycemic hyperinsulinemic hyperaminoacidemic clamp, together with Western blot analysis of protein kinase B (PKB), mTOR, 4E-BP1, and S6K1 phosphorylation. In basal state, muscle protein FSR was reduced in elderly in comparison with young subjects (0.061+/-0.004% per hour) vs 0.082+/-0.010% per hour, elderly vs. young, P<0.05). During clamp, muscle protein FSR was stimulated in young (0.119+/-0.006% per hour; P<0.05), but this response was significantly lower in elderly subjects (0.084+/-0.005% per hour, P<0.05 vs young subjects). Phosphorylation of PKB, mTOR, and 4E-BP1 were similarly increased by insulin and amino acid in both groups, except for S6K1 phosphorylation, which was not stimulated in elderly subjects. In conclusion, 1) response of muscle protein synthesis to insulin and amino acid is impaired in elderly humans; 2) a defect in S6K1 pathway activation may be responsible for this alteration. This modification is a mechanistic basis of sarcopenia development during aging.
与年龄相关的肌肉蛋白丢失可能涉及翻译因子失调导致的肌肉蛋白合成对合成代谢因子的反应降低。为验证这一假设，我们在6名年轻受试者（25±1岁；均值±标准误）和8名老年受试者（72±2岁）的正常血糖高胰岛素高氨基酸钳夹实验期间，同时研究了肌肉蛋白合成以及一些与胰岛素信号转导相关因子的表达。在股外侧肌测量基础状态以及正常血糖高胰岛素高氨基酸钳夹期间L-[1-13C]亮氨酸掺入肌肉蛋白的情况（分数合成率，FSR），同时采用蛋白质免疫印迹法分析蛋白激酶B（PKB）、哺乳动物雷帕霉素靶蛋白（mTOR）、真核翻译起始因子4E结合蛋白1（4E-BP1）和核糖体蛋白S6激酶1（S6K1）的磷酸化情况。在基础状态下，老年受试者的肌肉蛋白FSR低于年轻受试者（每小时0.061±0.004% 对比每小时0.082±0.010%，老年组对比年轻组，P<0.05）。在钳夹期间，年轻受试者的肌肉蛋白FSR受到刺激（每小时0.119±0.006%；P<0.05），但老年受试者的这种反应明显较低（每小时0.084±0.005%，与年轻受试者相比P<0.05）。两组中PKB、mTOR和4E-BP1的磷酸化均被胰岛素和氨基酸类似地增加，但老年受试者中S6K1的磷酸化未受到刺激。总之，1）老年人体内肌肉蛋白合成对胰岛素和氨基酸的反应受损；2）S6K1途径激活缺陷可能是这种改变的原因。这种变化是衰老过程中肌肉减少症发生的机制基础。
