Department of Life Sciences, Sport and Exercise Science Research Center, University of Roehampton, London, UK.
Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
J Physiol. 2020 Dec;598(24):5701-5716. doi: 10.1113/JP280441. Epub 2020 Nov 2.
Patients with renal failure undergoing maintenance haemodialysis are associated with insulin resistance and protein metabolism dysfunction. Novel research suggests that disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in haemodialysis. ILK, PINCH1 and pFAK were significantly decreased in haemodialysis compared to controls, whereas Rac1 and Akt2 showed no different between groups. Rac1 deletion in the Rac1 knockout model did not alter the expression of integrin-associated proteins. Phenylalanine kinetics were reduced in the haemodialysis group at 30 and 60 min post meal ingestion compared to controls; both groups showed similar levels of insulin sensitivity and β-cell function. Key proteins in the integrin-cytoskeleton linkage are reduced in haemodialysis patients, suggesting for the first time that integrin-associated proteins dysfunction may contribute to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients.
Muscle atrophy, insulin resistance and reduced muscle phosphoinositide 3-kinase-Akt signalling are common characteristics of patients undergoing maintenance haemodialysis (MHD). Disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in MHD patients. Eight MHD patients (age: 56 ± 5 years: body mass index: 32 ± 2 kg m ) and non-diseased controls (age: 50 ± 2 years: body mass index: 31 ± 1 kg m ) received primed continuous l-[ring- H ]phenylalanine before consuming a mixed meal. Phenylalanine metabolism was determined using two-compartment modelling. Muscle biopsies were collected prior to the meal and at 300 min postprandially. In a separate experiment, skeletal muscle tissue from muscle-specific Rac1 knockout (Rac1 mKO) was harvested to investigate whether Rac1 depletion disrupted the cytoskeleton-integrin linkage, allowing for cross-model examination of proteins of interest. ILK, PINCH1 and pFAK were significantly lower in MHD (P < 0.01). Rac1 and Akt showed no difference between groups for the human trial. Rac1 deletion in the Rac1 mKO model did not alter the expression of integrin-associated proteins. Phenylalanine rates of appearance and disappearance, as well as metabolic clearance rates, were lower in the MHD group at 30 and 60 min post meal ingestion compared to controls (P < 0.05). Both groups showed similar levels of insulin sensitivity and β-cell function. Key proteins in the integrin-cytoskeleton linkage are reduced in MHD patients, suggesting for the first time that integrin-associated proteins dysfunction may contribute to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients.
接受维持性血液透析的肾衰竭患者存在胰岛素抵抗和蛋白质代谢功能障碍。新的研究表明，骨架肌细胞中细胞外基质与细胞骨架之间跨膜蛋白连接的破坏可能导致血液透析患者氨基酸代谢和胰岛素抵抗降低。与对照组相比，血液透析患者中 ILK、PINCH1 和 pFAK 明显降低，而 Rac1 和 Akt2 在组间无差异。Rac1 敲除模型中 Rac1 的缺失并未改变整合素相关蛋白的表达。与对照组相比，血液透析组在餐后 30 和 60 分钟时苯丙氨酸动力学降低；两组的胰岛素敏感性和β细胞功能相似。血液透析患者中整合素-细胞骨架连接的关键蛋白减少，这首次表明整合素相关蛋白功能障碍可能导致苯丙氨酸通量降低，而不影响血液透析患者的胰岛素抵抗。
肌肉萎缩、胰岛素抵抗和磷酸肌醇 3-激酶-akt 信号转导降低是接受维持性血液透析（MHD）患者的共同特征。骨架肌细胞中细胞外基质与细胞骨架之间跨膜蛋白连接的破坏可能导致 MHD 患者氨基酸代谢和胰岛素抵抗降低。8 名 MHD 患者（年龄：56±5 岁；体重指数：32±2kg/m ）和非疾病对照组（年龄：50±2 岁；体重指数：31±1kg/m ）在进食混合餐之前接受连续预脉冲 l-[环- H ]苯丙氨酸。使用双室模型确定苯丙氨酸代谢。在进餐后 300 分钟前采集肌肉活检。在另一个实验中，从肌肉特异性 Rac1 敲除（Rac1 mKO）中收获骨骼肌组织，以研究 Rac1 耗竭是否破坏细胞骨架-整合素连接，从而允许跨模型检查感兴趣的蛋白质。ILK、PINCH1 和 pFAK 在 MHD 中明显降低（P<0.01）。人类试验中 Rac1 和 Akt 在组间无差异。Rac1 mKO 模型中 Rac1 的缺失并未改变整合素相关蛋白的表达。与对照组相比，血液透析组在进餐后 30 和 60 分钟时苯丙氨酸的出现率和消失率以及代谢清除率均降低（P<0.05）。两组的胰岛素敏感性和β细胞功能相似。MHD 患者中整合素-细胞骨架连接的关键蛋白减少，这首次表明整合素相关蛋白功能障碍可能导致苯丙氨酸通量降低，而不影响血液透析患者的胰岛素抵抗。
