Acute endurance exercise modulates growth differentiation factor 11 in cerebrospinal fluid of healthy young adults

Abstract

Objective: Strong evidence supports the benefits of exercise for healthy ageing, including reduced risk of neurodegenerative diseases. Recent studies suggested interorgan crosstalk as a key element of systemic adaptive response, however, the role of specific molecules in mediating exercise effects on the human brain are not fully understood. In the present study, we explored the exercise-related regulation of Growth Differentiation Factor 11 (GDF11) in cerebrospinal fluid (CSF) and blood.

Methods: The samples of serum, plasma and CSF were obtained before and 60min after acute exercise (90min run) from twenty healthy young individuals. Additional serum and plasma samples were collected immediately after run. GDF11 protein content (immunoblotting), body composition (bioelectrical impedance), physical fitness (VO₂max, cycle spiroergometry) and cognitive functions (standardized computerized tests, Cogstate) were evaluated.

Results: Running decreased GDF11 protein content in CSF (-20.6%. p=0.046), while GDF11 in plasma and serum were not regulated. Two GDF11-specific antibodies of different origin were used to corroborate this result. Individuals with higher physical fitness displayed greater exercise-induced decrease of GDF11 in CSF than those with lower physical fitness (p=0.025). VO₂max correlated positively with GDF11 in serum (r=0.63, p=0.020) as well as with the exercise-induced change in GDF11 levels in CSF (r=0.59, p=0.042). Indirect measure of blood-brain barrier permeability (i.e. CSF/serum albumin ratio) tended to positively correlate with CSF/serum GDF11 ratio (p=0.060). CSF levels of GDF11 correlated positively with cognitive functions, including working memory, both before and after run (p<0.05).

Conclusion: Running-induced down-regulation of the GDF11 protein in the cerebrospinal fluid of healthy young individuals indicates the potential role of GDF11 in the exercise-induced cross-talk between periphery and the brain.

Keywords: GDF11; cerebrospinal fluid; exercise; growth differentiation factor 11; running.

Figure 1

An acute bout of endurance exercise (90 min run) modified the levels of GDF11 in cerebrospinal fluid but not in circulation of healthy trained volunteers. GDF11 levels were assessed by immunoblotting, using three different primary antibodies: (A) GDF11-specific N-terminus antibody (CSF, n=12/12, B/R, p=0.046); (B) GDF11-specific C-terminus antibody (CSF, n=13/13, B/R, p=0.008); (C) GDF11/8 antibody (CSF, n=12/12, B/R, p=0.065); (D) GDF11-specific N-terminus antibody (serum, n= 14/14/14, B/0/R); (E) GDF11-C-terminus antibody (plasma, n=13/13/13, B/0/R); (F) GDF11-specific N-terminus antibody (plasma, n=14/14/13, B/0/R); Due to the lack of space, molecular weight ladders are not visible in Figures 1D–F and therefore, the molecular weights of GDF11 are in this case approximate, based on our validation studies of antibodies. B, Basal, before run; R, after run; A.U., signal intensity; GDF, Growth Differentiation Factor. Immunoblotting of all samples was performed under identical conditions. Statistical differences were analysed using paired Student’s t-test. *p<0.05, **p<0.01, #p<0.1 (A–C).

Figure 2

Running-induced decrease of blood-brain barrier permeability (CSF/serum albumin ratio). n=17. (albumin values were not measured in CSF of one individual, and two individuals had CSF available only after the run) (A); its association with CSF/serum GDF11 ratio (B); and CSF/serum GDF11/8 ratio (C). CSF, Cerebrospinal Fluid; GDF, Growth Differentiation Factor. ***p<0.001; Open circles - before run; Full circles - after run.

Figure 3

Heat map depicting associations between levels of GDF11 and clinical parameters, as well as their running-induced changes. Data were analyzed using GDF11-specific N-terminus antibody (paired serum samples n=14; paired CSF samples n=12, unpaired CSF samples available only after run n=2). BMI, body mass index; CSF, cerebrospinal fluid; GDF, Growth Differentiation Factor; HRmax, maximal heart rate; S-CK, serum creatinkinase; R, correlation coefficient; VO₂max, maximal aerobic capacity. Coefficients of significant correlations (p<0.05) or trends (p<0.1) are presented in numbers.