Exercise induction of key transcriptional regulators of metabolic adaptation in muscle is preserved in type 2 diabetes

Rugivan Sabaratnam, Andreas J Pedersen, Tilde V Eskildsen, Jonas M Kristensen, Jørgen F P Wojtaszewski, Kurt Højlund

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

CONTEXT: Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. Regular exercise improves insulin sensitivity, mitochondrial function, and energy metabolism. Thus, an impaired response to exercise may contribute to insulin resistance. OBJECTIVE: We hypothesized that key transcriptional regulators of metabolic adaptation to exercise show an attenuated response in skeletal muscle in T2D. DESIGN AND PATIENTS: Skeletal muscle biopsies were obtained from 13 patients with T2D and 14 age- and weight-matched controls before, immediately after 1 hour acute exercise (70% maximal pulmonary oxygen uptake), and 3 hours into recovery to examine mRNA expression of key transcription factors and downstream targets and activity of key upstream kinases underlying the metabolic adaptation to exercise. RESULTS: Acute exercise increased gene expression of the nuclear hormone receptor 4A (NR4A) subfamily (∼4- to 36-fold) and other key transcription factors, including ATF3, EGR1, JUNB, SIK1, PPARA, and PPARG (∼1.5- to 12-fold), but with no differences between groups. The expression of NR4A1 (approximately eightfold) and NR4A3 (∼75-fold) was further increased 3 hours into recovery, whereas most muscle transcripts sustained elevated or returned to basal levels, again with no differences between groups. Muscle expression of HKII and SLC2A4 and hexokinase II protein content were reduced in patients with T2D. The phosphorylation of p38 MAPK, Erk1/2, Ca2+/calmodulin-dependent kinase II, and cAMP-responsive element-binding protein was equally increased in response to exercise and/or recovery in both groups. CONCLUSION: Acute exercise elicits a pronounced and overall similar increase in expression of key transcription factors and activation of key upstream kinases involved in muscle metabolic adaptation to exercise in patients with T2D and weight-matched controls.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume104
Issue number10
Pages (from-to)4909-4920
ISSN0021-972X
DOIs
Publication statusPublished - 1. Oct 2019

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Medical problems
Type 2 Diabetes Mellitus
Muscle
Exercise
Muscles
Transcription Factors
Phosphotransferases
Insulin
Recovery
Insulin Resistance
Skeletal Muscle
Phosphorylation
Hexokinase
Biopsy
p38 Mitogen-Activated Protein Kinases
Calmodulin
Cytoplasmic and Nuclear Receptors
Gene expression
Weights and Measures
Carrier Proteins

Cite this

@article{341bffdeb81d4a1da80fbce7399b98b3,
title = "Exercise induction of key transcriptional regulators of metabolic adaptation in muscle is preserved in type 2 diabetes",
abstract = "CONTEXT: Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. Regular exercise improves insulin sensitivity, mitochondrial function, and energy metabolism. Thus, an impaired response to exercise may contribute to insulin resistance. OBJECTIVE: We hypothesized that key transcriptional regulators of metabolic adaptation to exercise show an attenuated response in skeletal muscle in T2D. DESIGN AND PATIENTS: Skeletal muscle biopsies were obtained from 13 patients with T2D and 14 age- and weight-matched controls before, immediately after 1 hour acute exercise (70{\%} maximal pulmonary oxygen uptake), and 3 hours into recovery to examine mRNA expression of key transcription factors and downstream targets and activity of key upstream kinases underlying the metabolic adaptation to exercise. RESULTS: Acute exercise increased gene expression of the nuclear hormone receptor 4A (NR4A) subfamily (∼4- to 36-fold) and other key transcription factors, including ATF3, EGR1, JUNB, SIK1, PPARA, and PPARG (∼1.5- to 12-fold), but with no differences between groups. The expression of NR4A1 (approximately eightfold) and NR4A3 (∼75-fold) was further increased 3 hours into recovery, whereas most muscle transcripts sustained elevated or returned to basal levels, again with no differences between groups. Muscle expression of HKII and SLC2A4 and hexokinase II protein content were reduced in patients with T2D. The phosphorylation of p38 MAPK, Erk1/2, Ca2+/calmodulin-dependent kinase II, and cAMP-responsive element-binding protein was equally increased in response to exercise and/or recovery in both groups. CONCLUSION: Acute exercise elicits a pronounced and overall similar increase in expression of key transcription factors and activation of key upstream kinases involved in muscle metabolic adaptation to exercise in patients with T2D and weight-matched controls.",
author = "Rugivan Sabaratnam and Pedersen, {Andreas J} and Eskildsen, {Tilde V} and Kristensen, {Jonas M} and Wojtaszewski, {J{\o}rgen F P} and Kurt H{\o}jlund",
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doi = "10.1210/jc.2018-02679",
language = "English",
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pages = "4909--4920",
journal = "Journal of Clinical Endocrinology and Metabolism",
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Exercise induction of key transcriptional regulators of metabolic adaptation in muscle is preserved in type 2 diabetes. / Sabaratnam, Rugivan; Pedersen, Andreas J; Eskildsen, Tilde V; Kristensen, Jonas M; Wojtaszewski, Jørgen F P; Højlund, Kurt.

In: The Journal of clinical endocrinology and metabolism, Vol. 104, No. 10, 01.10.2019, p. 4909-4920.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Exercise induction of key transcriptional regulators of metabolic adaptation in muscle is preserved in type 2 diabetes

AU - Sabaratnam, Rugivan

AU - Pedersen, Andreas J

AU - Eskildsen, Tilde V

AU - Kristensen, Jonas M

AU - Wojtaszewski, Jørgen F P

AU - Højlund, Kurt

N1 - Copyright © 2019 Endocrine Society.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - CONTEXT: Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. Regular exercise improves insulin sensitivity, mitochondrial function, and energy metabolism. Thus, an impaired response to exercise may contribute to insulin resistance. OBJECTIVE: We hypothesized that key transcriptional regulators of metabolic adaptation to exercise show an attenuated response in skeletal muscle in T2D. DESIGN AND PATIENTS: Skeletal muscle biopsies were obtained from 13 patients with T2D and 14 age- and weight-matched controls before, immediately after 1 hour acute exercise (70% maximal pulmonary oxygen uptake), and 3 hours into recovery to examine mRNA expression of key transcription factors and downstream targets and activity of key upstream kinases underlying the metabolic adaptation to exercise. RESULTS: Acute exercise increased gene expression of the nuclear hormone receptor 4A (NR4A) subfamily (∼4- to 36-fold) and other key transcription factors, including ATF3, EGR1, JUNB, SIK1, PPARA, and PPARG (∼1.5- to 12-fold), but with no differences between groups. The expression of NR4A1 (approximately eightfold) and NR4A3 (∼75-fold) was further increased 3 hours into recovery, whereas most muscle transcripts sustained elevated or returned to basal levels, again with no differences between groups. Muscle expression of HKII and SLC2A4 and hexokinase II protein content were reduced in patients with T2D. The phosphorylation of p38 MAPK, Erk1/2, Ca2+/calmodulin-dependent kinase II, and cAMP-responsive element-binding protein was equally increased in response to exercise and/or recovery in both groups. CONCLUSION: Acute exercise elicits a pronounced and overall similar increase in expression of key transcription factors and activation of key upstream kinases involved in muscle metabolic adaptation to exercise in patients with T2D and weight-matched controls.

AB - CONTEXT: Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. Regular exercise improves insulin sensitivity, mitochondrial function, and energy metabolism. Thus, an impaired response to exercise may contribute to insulin resistance. OBJECTIVE: We hypothesized that key transcriptional regulators of metabolic adaptation to exercise show an attenuated response in skeletal muscle in T2D. DESIGN AND PATIENTS: Skeletal muscle biopsies were obtained from 13 patients with T2D and 14 age- and weight-matched controls before, immediately after 1 hour acute exercise (70% maximal pulmonary oxygen uptake), and 3 hours into recovery to examine mRNA expression of key transcription factors and downstream targets and activity of key upstream kinases underlying the metabolic adaptation to exercise. RESULTS: Acute exercise increased gene expression of the nuclear hormone receptor 4A (NR4A) subfamily (∼4- to 36-fold) and other key transcription factors, including ATF3, EGR1, JUNB, SIK1, PPARA, and PPARG (∼1.5- to 12-fold), but with no differences between groups. The expression of NR4A1 (approximately eightfold) and NR4A3 (∼75-fold) was further increased 3 hours into recovery, whereas most muscle transcripts sustained elevated or returned to basal levels, again with no differences between groups. Muscle expression of HKII and SLC2A4 and hexokinase II protein content were reduced in patients with T2D. The phosphorylation of p38 MAPK, Erk1/2, Ca2+/calmodulin-dependent kinase II, and cAMP-responsive element-binding protein was equally increased in response to exercise and/or recovery in both groups. CONCLUSION: Acute exercise elicits a pronounced and overall similar increase in expression of key transcription factors and activation of key upstream kinases involved in muscle metabolic adaptation to exercise in patients with T2D and weight-matched controls.

U2 - 10.1210/jc.2018-02679

DO - 10.1210/jc.2018-02679

M3 - Journal article

VL - 104

SP - 4909

EP - 4920

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 10

ER -