GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

Abstract

Growth differentiation factor 15 (GDF15) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether GDF15 is beneficial or detrimental. The aim of the study was to analyse the levels of circulating GDF15 in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of GDF15 was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of GDF15 increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating GDF15 is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of GDF15 plasma levels, that after the race are similar to that of patients. Moreover, GDF15 plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that GDF15 is associated with decreased muscle performance and increased inflammation.

Altered GDF15 and FGF21 Levels in Response to Strenuous Exercise: A Study in Marathon Runners

“…In these reports, the increase in GDF15 was around 1.5-to 2-fold, which is much less than the more than fourfold increase found here after marathon race-associated strenuous exercise. Only a study in spartathlon runner found a rise in GDF15 levels in the fourfold range found here for marathon runners (Tchou et al, 2009) whereas around threefold increase in GDF51 levels were reported after a long distance cycling race (Conte et al, 2020). During the editorial processing of the current article, a study in Marathon runners in Poland has been reported (Kaleta-Duss et al, 2020) showing a rise in GDF15 levels immediately after the race and normalization thereafter, confirming our findings.…”

“…Numerous studies have reported that FGF21 levels increase in response to experimental acute exercise (Cuevas-Ramos et al, 2012;Kim et al, 2013;Hansen et al, 2015Hansen et al, , 2016Slusher et al, 2015;Tanimura et al, 2016;Morville et al, 2018;Sargeant et al, 2018). GDF15 has also been reported to exhibit transient elevations following an experimental single bout of exercise (Kleinert et al, 2018), a cycling race (Conte et al, 2020) and relatively time-limited sports activities such as a soccer match (Sanchis-Gomar et al, 2013) or a training session of rugby players (Galliera et al, 2014). Increased levels of GDF15 in athletes immediately after a 247-km race (the so-called Spartathlon) has also been reported (Tchou et al, 2009).…”

The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia

“…The cachexia-induced muscle loss protection suggests a role for GDF15 in muscle mass maintenance. Moreover, GDF15 muscle and serum levels inversely correlate with muscle cross-sectional area in chronic obstructive pulmonary disease (COPD) patients [ 126 ] and with muscle force in lower limb mobility impairments [ 127 ]. Moreover, the overexpression of GDF15 in muscle is sufficient to induce muscle atrophy [ 126 ], likely by FoxO1 and SMAD3 activation [ 128 ].…”

Effects of Exercise Intervention on Mitochondrial Stress Biomarkers in Metabolic Syndrome Patients: A Randomized Controlled Trial

“…Consistently, basal circulating GDF15 levels were higher in physically inactive patients with impaired mobility causing chronic walking or exercising inabilities. Contrarily, basal circulating GDF15 levels were lower in active cyclists when compared to age-matched control counterparts [ 55 ]. Taken together, these findings imply a link between the systemic response to mitochondrial stress and the muscle-mediated metabolic fitness.…”