Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance hemodialysis patients.

KEY POINTS Patients with renal failure undergoing maintenance hemodialysis 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 hemodialysis. ILK, PINCH1 and pFAKTyr397 were significantly decreased in hemodialysis 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 hemodialysis group at 30 and 60 minutes after 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 hemodialysis patients, suggesting for the first time that integrin-associated proteins dysfunction may contribute to reduced phenylalanine flux without affecting insulin resistance in hemodialysis patients. ABSTRACT Background Muscle atrophy, insulin resistance and reduced muscle PI3K-Akt signaling are common characteristics of patients undergoing maintenance hemodialysis (MHD). Disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix (ECM) in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in MHD patients. Study Design Eight MHD patients (age: 56±5 y: BMI: 32±2 kg/m2 ) and non-diseased controls (age: 50±2 y: BMI: 31±1 kg/m2 ) received primed continuous L-[ring-2 H5 ]phenylalanine before consuming a mixed meal. Phenylalanine metabolism was determined using two-compartment modelling. Muscle biopsies were collected prior to and at 300 minutes postprandial. 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. Results ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P<0.01). Rac1 and Akt showed no different 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 (Ra ), disappearance (Rd ) and metabolic clearance rates (MCR) were lower in the MHD group at 30 and 60 minutes after meal ingestion compared to controls (P<0.05). Both groups showed similar levels of insulin sensitivity and β-cell function. Conclusions 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 hemodialysis patients. This article is protected by copyright. All rights reserved.