Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice

Abstract

Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57Bl/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.

Figure 1

Circulating GDF15 is not affected by acute treadmill exercise or long-term voluntary wheel running (VWR) in mice. (a) Study setup: Male mice were fed a semisynthetic low fat diet throughout life. Half of the mice were provided a running wheel from 7 wks of age (active group). All mice were subjected to an exhaustive treadmill test at 15 weeks of age and groups of mice sacrificed before (basal), immediately (0 hr post-run), and 3 hours (3 hr post-run) after the exercise bout, respectively; (b) Body weight development (n = 22–65 per group); (c) Body fat mass (n = 30–35) at 15 weeks of age; (d) Body lean mass (n = 30–35) at 15 weeks of age; (e) Development of exercise capacity determined by forced treadmill exercise until exhaustion (n = 9–10 per group); (f) Muscle citrate synthase (CS) activity (n = 12 per group); (g) Plasma creatine kinase (CK) (n = 4–7 per group); (h) Skeletal muscle (quadriceps) gene expression of Atf3, Pgc1α and Gdf15 (n = 5–6 per group); (i) Plasma GDF15 concentrations (n = 5–6 per group). Data are presented as mean + SEM (b–f,h) or as box plot with whiskers indicating minimum and maximum values (g,i); *p < 0.05, **p < 0.01, ***p < 0.001 compared to the respective sedentary group. ^§p < 0.05; ^§§p < 0.01; ^§§§p < 0.001 compared to basal control of the same activity group.

Figure 2

Obesity-induced circulating GDF15 is not affected by voluntary wheel running (VWR) independent of active lifestyle-induced adaptations. Male mice were fed a semisynthetic high fat diet throughout life to induce obesity. Half of the mice were provided a running wheel from 7 wks of age (active group) and all mice were subjected to an exhaustive treadmill test at 7, 15 and 35 wks of age. Animals were sacrificed one week after the last treadmill test. (a) Body mass and (b) fat mass development (n = 11–12 per group); (c) Body lean mass at time of sacrifice; (d) Development of exercise capacity determined by forced treadmill exercise until exhaustion (n = 12 per group); (e) Usage of running wheel on three consecutive days in week 11 and week 22 of age (n = 8 per group); (f) Plasma lactate levels measured immediately after the exhaustive exercise bout at 15 and 35 wks of age (n = 12–13 per group); (g) Blood glucose, and (h) plasma insulin during an oral glucose tolerance test performed in week 32 (n = 8–12 per group); (i) Plasma leptin levels (n = 11 per group); (j) Muscle (quadriceps) gene expression and (k) Gdf15 gene expression in liver, quadriceps (Quad) and epididymal white adipose tissue (eWAT) (n = 11 per group); (l) Plasma GDF15 levels (n = 11 per group). Data are presented as mean + SEM (a–h,j,k) or as box plot with whiskers indicating minimum and maximum values (i,l). When SEM is not visible it lies within the symbol size. *p < 0.05; **p < 0.01; **p < 0.001 compared to respective sedentary group.

Figure 3

GDF15 ablation has no effect on exercise performance but modulates muscle exercise response. Adult male GDF15-Ko (KO) and wild type (WT) mice were subjected to an exhaustive treadmill exercise test and sacrificed 5 hours (5 hr post-run) after the exercise bout. (a) Body mass; (b) body fat mass; (c) body lean mass; (d) exercise capacity (distance run); (e) basal and post exercise plasma GDF15 in WT mice; (f) skeletal muscle (quadriceps) gene expression of Atf3, Pgc1α and Gdf15 and (g) skeletal muscle (quadriceps) mRNA levels of UPR marker genes. n = 5–10 per group; data presented as mean + SEM or as box plot with whiskers indicating minimum and maximum values (e); *p < 0.05, **p < 0.01, ***p < 0.001 compared to non-exercised control if not otherwise indicated. n.d.: non detectable.