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 W.A.

Abstract

Key points: 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 pFAKTyr397 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. Abstract: 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–2) and non-diseased controls (age: 50 ± 2 years: body mass index: 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 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 pFAKTyr397 were significantly lower in MHD (P 

Citation

Draicchio, F., van Vliet, S., Ancu, O., Paluska, S. A., Wilund, K. R., Mickute, M., …Mackenzie, R. W. (2020). Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance haemodialysis patients. The Journal of physiology, 598(24), 5701-5716. https://doi.org/10.1113/JP280441

• Journal Article Type: Article
• Acceptance Date: Sep 9, 2020
• Online Publication Date: Sep 24, 2020
• Publication Date: Dec 15, 2020
• Deposit Date: May 15, 2021
• Publicly Available Date: May 17, 2021
• Journal: Journal of Physiology
• Print ISSN: 0022-3751
• Electronic ISSN: 1469-7793
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 598
• Issue: 24
• Pages: 5701-5716
• DOI: https://doi.org/10.1113/JP280441
• Keywords: Cytoskeleton; Haemodialysis; ILK; Insulin; Integrins; Metabolism; Phenylalanine; PINCH; Rac1
• Public URL: https://hull-repository.worktribe.com/output/3671076