Fitness Shifts the Balance of BDNF and IL-6 from Inflammation to Repair among People with Progressive Multiple Sclerosis

Abstract

Physical sedentarism is linked to elevated levels of circulating cytokines, whereas exercise upregulates growth-promoting proteins such as brain-derived neurotrophic factor (BDNF). The shift towards a 'repair' phenotype could protect against neurodegeneration, especially in diseases such as multiple sclerosis (MS). We investigated whether having higher fitness or participating in an acute bout of maximal exercise would shift the balance of BDNF and interleukin-6 (IL-6) in serum samples of people with progressive MS (n = 14), compared to matched controls (n = 8). Participants performed a maximal graded exercise test on a recumbent stepper, and blood samples were collected at rest and after the test. We assessed walking speed, fatigue, and maximal oxygen consumption (V·O2max). People with MS achieved about 50% lower V·O2max (p = 0.003) than controls. At rest, there were no differences in BDNF between MS and controls; however, IL-6 was significantly higher in MS. Higher V·O2max was associated with a shift in BDNF/IL-6 ratio from inflammation to repair (R = 0.7, p = 0.001) when considering both groups together. In the MS group, greater ability to upregulate BDNF was associated with faster walking speed and lower vitality. We present evidence that higher fitness indicates a shift in the balance of blood biomarkers towards a repair phenotype in progressive MS.

Keywords: biomarkers; brain-derived neurotrophic factor; cytokines; fitness; inflammation; interleukin-6; multiple sclerosis; neurodegeneration; neurotrophins; rehabilitation.

Figure 1

Blood marker responses to graded exercise test. Data presented as individual values. (a,b): Serum levels of brain-derived neurotrophic factor (BDNF) (ng·mL⁻¹) in MS and controls; (c,d): serum levels of interleukin-6 (IL-6) (ng·mL⁻¹) in MS and controls; (e,f): BDNF/IL-6 ratios in MS and controls; p values are from related-samples Wilcoxon signed-rank tests.

Figure 2

Relationships between biomarkers and functional measures when considering MS and controls together. Data presented as individual values. (a) Relationship between self-selected walking speed and resting BDNF; (b) relationship between vitality subscale on short form–36 and resting BDNF; (c) relationship between maximal oxygen consumption (${\displaystyle \stackrel{·}{\mathrm{V}}{\mathrm{O}}_2}$) during graded exercise test (GXT) and resting BDNF; (d) relationship between self-selected walking speed and resting IL-6; (e) relationship between vitality subscale on short form–36 and resting IL-6; (f) relationship between maximal ${\displaystyle \stackrel{·}{\mathrm{V}}{\mathrm{O}}_2}$ during GXT and resting IL-6; (g) relationship between self-selected walking speed and resting BDNF/IL-6 ratio; (h) relationship between vitality subscale on short form–36 and resting BDNF/IL-6 ratio; (i) relationship between maximal ${\displaystyle \stackrel{·}{\mathrm{V}}{\mathrm{O}}_2}$ during GXT and resting BDNF/IL-6 ratio; r and p values are from Spearman’s rank correlation coefficient.

Figure 3

Relationships between exercise-induced BDNF (in ng·mL⁻¹) and functional measures in participants with MS. Data presented as individual values. (a) Relationship between self-selected walking speed and exercise-induced BDNF; (b) relationship between vitality subscale on short form–36 and exercise-induced BDNF; (c) relationship between maximal ${\displaystyle \stackrel{·}{\mathrm{V}}{\mathrm{O}}_2}$ during GXT and exercise-induced BDNF; (d) relationship between maximal heart rate during GXT and exercise-induced BDNF; the r and p values are from Spearman’s rank correlation coefficient.