Acute Exercise Increases GDF15 and Unfolded Protein Response/Integrated Stress Response in Muscle in Type 2 diabetes

Rugivan Sabaratnam; Jonas M Kristensen; Andreas J T Pedersen; Rikke Kruse; Aase Handberg; Jørgen F P Wojtaszewski; Kurt Højlund

doi:10.1210/clinem/dgae032

Acute Exercise Increases GDF15 and Unfolded Protein Response/Integrated Stress Response in Muscle in Type 2 diabetes

J Clin Endocrinol Metab. 2024 Jan 18:dgae032. doi: 10.1210/clinem/dgae032. Online ahead of print.

Authors

Rugivan Sabaratnam^{1

2}, Jonas M Kristensen^{1

2

3}, Andreas J T Pedersen², Rikke Kruse^{1

2}, Aase Handberg^{4

5}, Jørgen F P Wojtaszewski³, Kurt Højlund^{1

2}

Affiliations

¹ Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark.
² Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark.
³ The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, DK-2100 Copenhagen, Denmark.
⁴ Department of Clinical Biochemistry, Aalborg University Hospital, North Denmark Region, DK-9000 Aalborg, Denmark.
⁵ Department of Clinical Medicine, Aalborg University, DK-9000 Aalborg, Denmark.

PMID: 38242693
DOI: 10.1210/clinem/dgae032

Abstract

Context: Regular exercise is a key prevention strategy for obesity and type 2 diabetes (T2D). Exerkines secreted in response to exercise or recovery may contribute to improved systemic metabolism. Conversely, an impaired exerkine response to exercise and recovery may contribute to cardiometabolic diseases.

Objective: We investigated if the exercise-induced regulation of the exerkine, growth/differentiation factor 15 (GDF15) and its putative upstream regulators of the unfolded protein response (UPR)/integrated stress response (ISR) is impaired in skeletal muscle in patients with T2D compared with weight-matched glucose-tolerant men.

Methods: Thirteen male patients with T2D and 14 age- and weight-matched overweight/obese glucose-tolerant men exercised at 70% of VO2max for 1-h. Blood and skeletal muscle biopsies were sampled before, immediately after, and 3-h into recovery. Serum and muscle transcript levels of GDF15 and key markers of UPR/ISR were determined. Additionally, protein/phosphorylation levels of key regulators in UPR/ISR were investigated.

Results: Acute exercise increased muscle gene expression and serum GDF15 levels in both groups. In recovery, muscle expression of GDF15 decreased toward baseline, whereas serum GDF15 remained elevated. In both groups, acute exercise increased the expression of UPR/ISR markers, including ATF4, CHOP, EIF2K3 (encoding PERK) and PPP1R15A (encoding GADD34), of which only CHOP remained elevated 3-h into recovery. Downstream molecules of the UPR/ISR including XBP1-U, XBP1-S, and EDEM1 were increased with exercise and 3-h into recovery in both groups. The phosphorylation levels of eIF2α-Ser51, a common marker of UPR and ISR, increased immediately after exercise in controls, but decreased 3-h into recovery in both groups.

Conclusion: In conclusion, exercise-induced regulation of GDF15 and key markers of UPR/ISR are not compromised in patients with type 2 diabetes compared with weight-matched controls.

Keywords: GDF15; Type 2 diabetes; UPR/ISR; exerkine; obesity; skeletal muscle.