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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 W.A.

Authors

Fulvia Draicchio

Stephan van Vliet

Oana Ancu

Scott A. Paluska

Kenneth R. Wilund

Monika Mickute

Thozhukat Sathyapalan

Derek Renshaw

Peter Watt

Lykke Sylow

Nicholas A. Burd

Richard W.A. Mackenzie



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

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https://creativecommons.org/licenses/by/4.0/

Copyright Statement
© 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.



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