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

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 hour. Blood and skeletal muscle biopsies were sampled before, immediately after, and 3 hours 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 hours into recovery. Downstream molecules of the UPR/ISR including XBP1-U, XBP1-S, and EDEM1 were increased with exercise and 3 hours into recovery in both groups. The phosphorylation levels of eIF2α-Ser51, a common marker of unfolded protein response (UPR) and ISR, increased immediately after exercise in controls, but decreased 3 hours 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 T2D compared with weight-matched controls.