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

Fulvia Draicchio, Stephan van Vliet, Oana Ancu, Scott Paluska, Kenneth Wilund, Monica Mickute, Thozhukat Sathyapalan, Derek Renshaw, Peter Watt, Lykke Sylow, Nicholas A. Burd, Richard Mackenzie

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
5 Downloads (Pure)

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 pFAK Tyr397 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- 2H 5]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 Tyr397 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.

Original languageEnglish
Pages (from-to)5701-5716
Number of pages16
JournalJournal of Physiology
Volume598
Issue number24
Early online date24 Sep 2020
DOIs
Publication statusPublished - 15 Dec 2020

Bibliographical note

© 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.

Keywords

  • hemodialysis; insulin; phenylalanine; metabolism; integrins; cytoskeleton; ILK; PINCH; Rac1.
  • integrins
  • PINCH
  • insulin
  • phenylalanine
  • cytoskeleton
  • haemodialysis
  • ILK
  • metabolism
  • Rac1

ASJC Scopus subject areas

  • Physiology

Fingerprint Dive into the research topics of 'Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance haemodialysis patients'. Together they form a unique fingerprint.

Cite this