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.

Keywords: GDF15; healthy aging; inflammation; physical activity; sedentarity; skeletal muscle.

Figure 1

Plasma levels of GDF15 increase with age and are negatively associated with active lifestyle. (A) Regression analysis of circulating GDF15 and age in cyclists, controls and patients. (B–D) Circulating plasma levels of GDF15 in young cyclists (T1), controls and patients (B); in adult cyclists (T1), controls and patients (C); in late adult cyclists (T1), controls and patients (D). Data are expressed as mean ± SE and p-values refer to Kruskal-Wallis test. (E) Circulating plasma levels of GDF15 in old controls and patients, data are expressed as mean ± SE and p-values refer to Mann-Whitney test. (F) Regression analysis of circulating GDF15 vs. quadriceps maximal torque normalized for age and vastus lateralis muscle thickness in patients.

Figure 2

GDF15 plasma levels in cyclists before and after the race. (A) The differences among plasma GDF15 levels before the race (T1), immediately after the race (T2), and after 18–24 h from the race (T3) were analyzed. Data are expressed as mean ± SE p-values refer to Friedman test. (B–D) Circulating plasma levels of GDF15 in young cyclists (T2), controls and patients (B); in adult cyclists (T2), controls and patients (C); in late adult cyclists (T2), controls and patients (D). Data are expressed as mean ± SE and p-values refer to Kruskal-Wallis test.

Figure 3

Regression analysis of GDF15 plasma levels with hematological parameters. (A–C) Regression analysis of circulating GDF15 levels and leukocytes (A), neutrophils (B), lymphocytes (C), in cyclists before the race (T1), immediately after the race (T2), and in patients.

Figure 4

Regression analysis of GDF15 plasma levels with hematological markers of cellular inflammation in cyclists before (T1) and immediately after (T2) the race. (A) Regression analysis of circulating GDF15 levels and neutrophil/lymphocyte ratio (NLR); (B) regression analysis of circulating GDF15 levels and platelet/lymphocyte ratio (PLR); (C) regression analysis of circulating GDF15 levels and systemic immune-inflammation index (SII).

Figure 5

Regression analysis of GDF15 plasma levels with estimated glomerular filtration rate (eGFR) and creatinine. (A,B) Regression analysis of circulating GDF15 and eGFR (A), creatinine (B) in cyclists before the race (T1), immediately after the race (T2).