Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance haemodialysis patients
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Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance haemodialysis patients. / Draicchio, Fulvia; van Vliet, Stephan; Ancu, Oana; Paluska, Scott A; Wilund, Kenneth R; Mickute, Monika; Sathyapalan, Thozhukat; Renshaw, Derek; Watt, Peter; Sylow, Lykke; Burd, Nicholas A; Mackenzie, Richard.
I: Journal of Physiology, Bind 598, Nr. 24, 2020, s. 5701-5716.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance haemodialysis patients
AU - Draicchio, Fulvia
AU - van Vliet, Stephan
AU - Ancu, Oana
AU - Paluska, Scott A
AU - Wilund, Kenneth R
AU - Mickute, Monika
AU - Sathyapalan, Thozhukat
AU - Renshaw, Derek
AU - Watt, Peter
AU - Sylow, Lykke
AU - Burd, Nicholas A
AU - Mackenzie, Richard
N1 - This article is protected by copyright. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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 in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in MHD patients. Eight MHD patients (age: 56±5 y: BMI: 32±2 kg/m-2) and non-diseased controls (age: 50±2 y: BMI: 31±1 kg/m-2) received primed continuous L-[ring-2H5 ]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 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. ILK, PINCH1 and pFAKTyr397 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.
AB - 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 in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in MHD patients. Eight MHD patients (age: 56±5 y: BMI: 32±2 kg/m-2) and non-diseased controls (age: 50±2 y: BMI: 31±1 kg/m-2) received primed continuous L-[ring-2H5 ]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 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. ILK, PINCH1 and pFAKTyr397 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.
KW - Faculty of Science
KW - Cytoskeleton
KW - Haemodialysis
KW - ILK
KW - Insulin
KW - Integrins
KW - Metabolism
KW - Phenylalanine
KW - PINCH
KW - Rac1
U2 - 10.1113/JP280441
DO - 10.1113/JP280441
M3 - Journal article
C2 - 32969494
VL - 598
SP - 5701
EP - 5716
JO - The Journal of Physiology
JF - The Journal of Physiology
SN - 0022-3751
IS - 24
ER -
ID: 249065770