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

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 Møller

AU - Wojtaszewski, Jørgen

AU - Højlund, Kurt

N1 - CURIS 2019 NEXS 295 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

C2 - 31135885

SN - 0021-972X

VL - 104

SP - 4909

EP - 4920

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 10

ER -