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

Fulvia Draicchio; Stephan  van Vlie; Oana Ancu; Scott  Paluska; Kenneth  Wilund; Monika Mickute; Thozhukat Sathyapalan; Derek Renshaw; Peter Watt; Lykke Sylow; Nicholas Burd; Richard Mackenzie

doi:10.1113/JP280441

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

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

Research output: Contribution to journal › Article › peer-review

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-2H5]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.Key Points•Patients in maintenance haemodialysis (MHD) are associated with insulin resistance and protein metabolism dysfunction.•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.•ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P<0.01) compared to controls, whereas Rac1 and Akt showed no different between groups.•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.•Key proteins in the integrin-cytoskeleton linkage are reduced in MHD patients, suggesting for the first time that integrin-associated proteins dysfunction contributes to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients.

Original language	English
Pages (from-to)	JP-RP-2020-280441R1
Journal	Journal of Physiology
DOIs	https://doi.org/10.1113/JP280441
Publication status	Published - 10 Oct 2020

Keywords

Endocrine
Metabolism
Extracellular matrix (ECM)

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https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP280441Licence: CC BY

Cite this

@article{b4bafc8e146142179569e9f049012a9b,

title = "Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance 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-2H5]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.Key Points•Patients in maintenance haemodialysis (MHD) are associated with insulin resistance and protein metabolism dysfunction.•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.•ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P<0.01) compared to controls, whereas Rac1 and Akt showed no different between groups.•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.•Key proteins in the integrin-cytoskeleton linkage are reduced in MHD patients, suggesting for the first time that integrin-associated proteins dysfunction contributes to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients.",

keywords = "Endocrine, Metabolism, Extracellular matrix (ECM)",

author = "Fulvia Draicchio and {van Vlie}, Stephan and Oana Ancu and Scott Paluska and Kenneth Wilund and Monika Mickute and Thozhukat Sathyapalan and Derek Renshaw and Peter Watt and Lykke Sylow and Nicholas Burd and Richard Mackenzie",

year = "2020",

month = oct,

day = "10",

doi = "10.1113/JP280441",

language = "English",

pages = "JP--RP--2020--280441R1",

journal = "Journal of Physiology",

issn = "1469-7793",

publisher = "Wiley",

}

TY - JOUR

T1 - Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance hemodialysis patients

AU - Draicchio, Fulvia

AU - van Vlie, Stephan

AU - Ancu, Oana

AU - Paluska, Scott

AU - Wilund, Kenneth

AU - Mickute, Monika

AU - Sathyapalan, Thozhukat

AU - Renshaw, Derek

AU - Watt, Peter

AU - Sylow, Lykke

AU - Burd, Nicholas

AU - Mackenzie, Richard

PY - 2020/10/10

Y1 - 2020/10/10

N2 - 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-2H5]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.Key Points•Patients in maintenance haemodialysis (MHD) are associated with insulin resistance and protein metabolism dysfunction.•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.•ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P<0.01) compared to controls, whereas Rac1 and Akt showed no different between groups.•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.•Key proteins in the integrin-cytoskeleton linkage are reduced in MHD patients, suggesting for the first time that integrin-associated proteins dysfunction contributes to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients.

AB - 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-2H5]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.Key Points•Patients in maintenance haemodialysis (MHD) are associated with insulin resistance and protein metabolism dysfunction.•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.•ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P<0.01) compared to controls, whereas Rac1 and Akt showed no different between groups.•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.•Key proteins in the integrin-cytoskeleton linkage are reduced in MHD patients, suggesting for the first time that integrin-associated proteins dysfunction contributes to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients.

KW - Endocrine

KW - Metabolism

KW - Extracellular matrix (ECM)

U2 - 10.1113/JP280441

DO - 10.1113/JP280441

M3 - Article

SN - 1469-7793

SP - JP-RP-2020-280441R1

JO - Journal of Physiology

JF - Journal of Physiology

ER -