FGF21 is Produced By Active Skeletal Muscle during Intense Exercise in Humans

Abstract

Fibroblast growth factor 21 (FGF21) is a peptide produced mostly by the liver and other tissues as skeletal muscle. Recent work supports that the main source of circulating FGF21 during exercise is the hepato-splanchnic circulation. Nevertheless, increased FGF21 mRNA has been reported in human skeletal muscle after prolonged exercise. Given the great increase of skeletal muscle blood flow during exercise, a small amount of FGF21 released by active skeletal muscles could have escaped detection by a-v differences. PURPOSE: to determine whether skeletal muscle produces FGF21 in response to exercise and the influence of muscle metabolism and oxygenation on this process. METHODS: Eleven volunteers performed incremental exercise (IE) to exhaustion in normoxia (Nx, PIO2:143 mmHg) and hypoxia (Hyp, PIO2:73 mmHg) while muscle metabolites and FGF21 protein expression (Western Blot) were measured before (control) and immediately after IE in Nx and Hyp. Immediately after IE, the circulation of one leg was instantaneously occluded (300 mmHg) and vastus lateralis muscle biopsies obtained after 10s from the occluded leg, and simultaneously from both legs at 60s. RESULTS: At 10s muscle lactate ([La]) was increased and phosphocreatine (PCr) and ATP reduced in Nx and Hyp, without differences between conditions. Muscle [La] was increased by 25% from 10 to 60s in the occluded leg (P<0.05) and unchanged in the non-occluded leg (+5% P=0.71). After 60s, PCr was reduced by 94 and 48%, in the occluded and non-occluded leg, respectively (P<0.05). Compared to pre-exercise, FGF21 protein expression was increased in the occluded leg by 55 and 57% at 10s and 60s, respectively (time effect P=0.02) and by 10% (P=0.42) in the non-occluded leg at 60s, without influence of PIO2. No association was observed between metabolite accumulation and FGF21 expression. CONCLUSIONS: FGF21 is produced during intense exercise in human skeletal muscle. The fact that FGF21 was not increased 60s after the end of exercise in the leg recovering with free circulation highlights the utility of total occlusion of the circulation to trap in the muscle myokines released in small amounts by the muscle during contractile activity. Funding: MINECO Ref.: DEP2015-71171-R