Exercising with blocked muscle glycogenolysis: Adaptation in the McArdle mouse

TY - JOUR

T1 - Exercising with blocked muscle glycogenolysis

T2 - Adaptation in the McArdle mouse

AU - Nielsen, Tue L

AU - Pinós, Tomàs

AU - Brull, Astrid

AU - Vissing, John

AU - Krag, Thomas O

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2018/1

Y1 - 2018/1

N2 - BACKGROUND: McArdle disease (glycogen storage disease type V) is an inborn error of skeletal muscle metabolism, which affects glycogen phosphorylase (myophosphorylase) activity leading to an inability to break down glycogen. Patients with McArdle disease are exercise intolerant, as muscle glycogen-derived glucose is unavailable during exercise. Metabolic adaptation to blocked muscle glycogenolysis occurs at rest in the McArdle mouse model, but only in highly glycolytic muscle. However, it is unknown what compensatory metabolic adaptations occur during exercise in McArdle disease.METHODS: In this study, 8-week old McArdle and wild-type mice were exercised on a treadmill until exhausted. Dissected muscles were compared with non-exercised, age-matched McArdle and wild-type mice for histology and activation and expression of proteins involved in glucose uptake and glycogenolysis.RESULTS: Investigation of expression and activation of proteins involved in glycolytic flux revealed that in glycolytic, but not oxidative muscle from exercised McArdle mice, the glycolytic flux had changed compared to that in wild-type mice. Specifically, exercise triggered in glycolytic muscle a differentiated activation of insulin receptor, 5' adenosine monophosphate-activated protein kinase, Akt and hexokinase II expression, while inhibiting glycogen synthase, suggesting that the need and adapted ability to take up blood glucose and use it for metabolism or glycogen storage is different among the investigated muscles.CONCLUSION: The main finding of the study is that McArdle mouse muscles appear to adapt to the energy crisis by increasing expression and activation of proteins involved in blood glucose metabolism in response to exercise in the same directional way across the investigated muscles.

AB - BACKGROUND: McArdle disease (glycogen storage disease type V) is an inborn error of skeletal muscle metabolism, which affects glycogen phosphorylase (myophosphorylase) activity leading to an inability to break down glycogen. Patients with McArdle disease are exercise intolerant, as muscle glycogen-derived glucose is unavailable during exercise. Metabolic adaptation to blocked muscle glycogenolysis occurs at rest in the McArdle mouse model, but only in highly glycolytic muscle. However, it is unknown what compensatory metabolic adaptations occur during exercise in McArdle disease.METHODS: In this study, 8-week old McArdle and wild-type mice were exercised on a treadmill until exhausted. Dissected muscles were compared with non-exercised, age-matched McArdle and wild-type mice for histology and activation and expression of proteins involved in glucose uptake and glycogenolysis.RESULTS: Investigation of expression and activation of proteins involved in glycolytic flux revealed that in glycolytic, but not oxidative muscle from exercised McArdle mice, the glycolytic flux had changed compared to that in wild-type mice. Specifically, exercise triggered in glycolytic muscle a differentiated activation of insulin receptor, 5' adenosine monophosphate-activated protein kinase, Akt and hexokinase II expression, while inhibiting glycogen synthase, suggesting that the need and adapted ability to take up blood glucose and use it for metabolism or glycogen storage is different among the investigated muscles.CONCLUSION: The main finding of the study is that McArdle mouse muscles appear to adapt to the energy crisis by increasing expression and activation of proteins involved in blood glucose metabolism in response to exercise in the same directional way across the investigated muscles.

KW - Animals

KW - Disease Models, Animal

KW - Glycogen/metabolism

KW - Glycogen Storage Disease Type V/metabolism

KW - Humans

KW - Mice

KW - Muscle, Skeletal/metabolism

KW - Physical Conditioning, Animal

U2 - 10.1016/j.ymgme.2017.11.006

DO - 10.1016/j.ymgme.2017.11.006

M3 - Journal article

C2 - 29174367

SN - 1096-7192

VL - 123

SP - 21

EP - 27

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 1

ER -