Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health?

Abstract

Key points• Contradictory findings have been reported concerning the function of irisin and its precursor gene, skeletal muscle FNDC5, in energy homeostasis and metabolic health, and the associated regulatory role of exercise and PGC-1α.• We analysed the effects of different short-and long-term exercise regimens on muscle FNDC5and PGC-1α, and serum irisin, and studied the associations of irisin and FNDC5 with health parameters.• FNDC5 and serum irisin did not change after acute aerobic, long-term endurance training or endurance training combined with resistance exercise (RE) training, or associate with metabolic disturbances. A single RE bout increased FNDC5 mRNA in young, but not older men (27 vs. 62 years). Changes in PGC-1α or serum irisin were not consistently accompanied by changes in FNDC5.• Our data suggest that the effects of exercise on FNDC5 and irisin are not consistent, and that their role in health is questionable. Moreover, the regulatory mechanisms should be studied further.Abstract Recently, contradictory findings have been reported concerning the function of irisin and its precursor gene, skeletal muscle FNDC5, in energy homeostasis, and the associated regulatory role of exercise and PGC-1α. We therefore evaluated whether muscle FNDC5 mRNA and serum irisin are exercise responsive and whether PGC-1α expression is associated with FNDC5 expression. The male subjects in the study performed single exercises: (1) 1 h low-intensity aerobic exercise (AE) (middle-aged, n = 17), (2) a heavy-intensity resistance exercise (RE) bout (young n = 10, older n = 11) (27 vs. 62 years), (3) long-term 21 weeks endurance exercise (EE) training alone (twice a week, middle-aged, n = 9), or (4) combined EE and RE training (both twice a week, middle-aged, n = 9). Skeletal muscle mRNA expression was analysed by quantitative PCR and serum irisin by ELISA. No significant changes were observed in skeletal muscle PGC-1α, FNDC5 and serum irisin after AE, EE training or combined EE + RE training. However, a single RE bout increased PGC-1α by 4-fold in young and by 2-fold in older men, while FNDC5 mRNA only increased in young men post-RE, by 1.

Irisin and FNDC5: effects of 12-week strength training, and relations to muscle phenotype and body mass composition in untrained women

“…Furthermore, we found FNDC5 expression to be closely correlated with proportions of aerobic muscle fibers in untrained (pre) but not in trained (post) muscle, suggesting that strength training has an intricate effect on irisin biology. Such a lack of a general training-associated FNDC5/irisin response was accompanied by a lack of PGC1α expression, and is in agreement with recent studies showing that neither acute training sessions nor prolonged periods of endurance training and/or strength training has an effect on FNDC5 expression (Timmons et al 2012;Pekkala et al 2013;Raschke et al 2013) or irisin secretion (Hecksteden et al 2013;Pekkala et al 2013) in men/mixed gender groups, in turn contrasting the premier data presented by Bostrom et al (2012). Importantly, as our data was sampled from subjects in a rested state, the current data does not make feasible analyses of effects of acute training sessions on FNDC5 expression or sirisin.…”

“…No association was found between s-irisin and changes in body mass composition. This lack of an irisin response is in line with previous findings (Pekkala et al 2013;Raschke et al 2013;Hecksteden et al 2013;Timmons et al 2012) and was seen despite evidence for extensive training-associated alterations in muscle properties, as suggested from increased LBM and a shift towards an aerobic muscle phenotype. The latter could have been expected to be accompanied by increased overall FNDC5 expression, as proportions of MyHC1/2A fibers was found to be positively correlated with FNDC5 expression in untrained pre biopsies.…”

“…An association between FNDC5 expression and aerobic fibers has indeed been indicated in rodents (Wrann et al 2013;Roca-Rivada et al 2013). Such an association may shed light on the previously observed individual variation in FNDC5/s-irisin abundances (Timmons et al 2012;Boström et al 2012;Pekkala et al 2013;Huh et al 2012). Moreover, FNDC5 expression may well vary between different groups of muscles, such as those of the upper and lower limbs, which are known to exhibit differences in biology, e.g.…”

“…As an example, Timmons et al (2012) failed to reproduce the training-induced increase in steady-state FNDC5 expression in a larger cohort of individuals, leading to debate concerning inaccuracies of current studies, related to both the choice of human subjects and to the choices of methodology for FNDC5 mRNA assessment (Timmons et al 2012;Boström et al 2012). This lack of effect of endurance training and/or strength training on FNDC5 expression (Pekkala et al 2013;Raschke et al 2013) or irisin serum levels (s-irisin) (Pekkala et al 2013;Hecksteden et al 2013) has been confirmed in recent studies, both on the level of steady-state abundances following prolonged training protocols (Pekkala et al 2013;Raschke et al 2013;Hecksteden et al 2013) and on the level of acutely induced expression following single sessions of training (Pekkala et al 2013). Raschke et al (2013) even suggested that the human FNDC5 gene represents a pseudogene, in which a mutation in its Kozak consensus sequence prohibits it from being effectively translated into protein.…”

“…These aberrances may of course be caused by per-chance statistical errors or technical flaws, perhaps related to dubious quantification of s-irisin (Raschke et al 2013;Erickson 2013). However, they may also hint towards between-groups or even between-individuals differences in irisin biology, for which observations have been made (Timmons et al 2012;Boström et al 2012;Pekkala et al 2013). Recently, Lee et al (2014) revitalized the potential significance of irisin in human medicine by demonstrating its natural induction in response to hypothermia and exercise, in turn inducing browning gene expression programs in adipocytes.…”