The catalytic subunit of the system L1 amino acid transporter (slc7a5) facilitates nutrient signalling in mouse skeletal muscle.
The catalytic subunit of the system L1 amino acid transporter (slc7a5) facilitates nutrient signalling in mouse skeletal muscle.
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DOI：
10.1371/journal.pone.0089547
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Taylor PM
中科院分区：
文献类型：
--
作者：
Poncet N;Mitchell FE;Ibrahim AF;McGuire VA;English G;Arthur JS;Shi YB;Taylor PM
系统L1型氨基酸转运蛋白在许多哺乳动物细胞类型中介导大分子中性氨基酸（LNAA）的转运。LNAA如亮氨酸是促进蛋白质合成和细胞生长的mTOR-S6 K信号通路的完全激活所需的。高亲和力系统L1的SLC 7A 5（LAT 1）催化亚基作为糖蛋白相关异源二聚体与多功能蛋白SLC 3A 2（CD 98）一起发挥功能。我们产生了一种floxed Slc 7a 5小鼠品系，当与表达由全局启动子驱动的Cre的小鼠杂交时，产生了没有明显表型的Slc 7a 5杂合敲除（Slc 7a 5 +/−）动物，尽管Slc 7a 5的纯合全局敲除是胚胎致死的。肌肉特异性（MCK Cre介导的）Slc 7a 5敲除（MS-Slc 7a 5-KO）小鼠用于研究通过SLC 7A 5转运蛋白的细胞内LNAA递送对于骨骼肌中mTOR-S6 K途径活化的作用。相对于野生型动物，在纯合MS-Slc 7a 5-KO小鼠中，通过腹膜内亮氨酸注射体内肌肉mTOR-S6 K（Thr 389磷酸化）的激活是钝化的。用含10%、20%或30%蛋白质的饲料喂养10周（至120日龄）的MS-Slc 7a 5-KO小鼠和野生型同窝仔的饲料摄入量和生长速率相似。在MS-Slc 7a 5-KO小鼠中，当膳食蛋白质含量从30%降低至10%时，腓肠肌中的Leu和Ile浓度降低了约40%。这些变化与来自MS-Slc 7a 5-KO小鼠的肌肉中S6 K Thr 389磷酸化降低>50%相关，表明mTOR-S6 K途径活化降低，尽管相同饮食的组之间的瘦组织质量没有显著差异。相对于对照动物，30%蛋白质饮食的MS-Slc 7a 5-KO小鼠表现出轻度胰岛素抵抗（例如，葡萄糖清除率降低，性腺脂肪贮库较大）。因此，SLC 7A 5调节小鼠中的LNA依赖性肌肉mTOR-S6 K信号传导，尽管它对于维持正常肌肉质量似乎是非必需的（或被例如SLC 7A 8（LAT 2）充分补偿）。
The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5+/−) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Muscle-specific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by ∼40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e.g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e.g. SLC7A8 (LAT2)) for maintenance of normal muscle mass.
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影响因子：
3.7
作者：
Macotela Y;Emanuelli B;Bång AM;Espinoza DO;Boucher J;Beebe K;Gall W;Kahn CR
通讯作者：
Kahn CR
DOI：
10.1083/jcb.200903131
发表时间：
2009-12-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Risson V;Mazelin L;Roceri M;Sanchez H;Moncollin V;Corneloup C;Richard-Bulteau H;Vignaud A;Baas D;Defour A;Freyssenet D;Tanti JF;Le-Marchand-Brustel Y;Ferrier B;Conjard-Duplany A;Romanino K;Bauché S;Hantaï D;Mueller M;Kozma SC;Thomas G;Rüegg MA;Ferry A;Pende M;Bigard X;Koulmann N;Schaeffer L;Gangloff YG
通讯作者：
Gangloff YG
DOI：
10.1152/ajpendo.00409.2012
发表时间：
2013-01-01
影响因子：
5.1
作者：
Kelleher, Andrew R.;Kimball, Scot R.;Jefferson, Leonard S.
通讯作者：
Jefferson, Leonard S.
影响因子：
16
作者：
Bruning, JC;Michael, MD;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
3.7
作者：
Binder E;Bermúdez-Silva FJ;André C;Elie M;Romero-Zerbo SY;Leste-Lasserre T;Belluomo I;Duchampt A;Clark S;Aubert A;Mezzullo M;Fanelli F;Pagotto U;Layé S;Mithieux G;Cota D
通讯作者：
Cota D