Irisin, a unique non-inflammatory myokine in stimulating skeletal muscle metabolism

Abstract

Exercise offers several benefits for health, including increased lean body mass and heightened energy expenditure, which may be partially attributable to secretory factors known as myokines. Irisin, a recently identified myokine, was shown to increase metabolic rate and mitochondrial content in both myocytes and adipocytes; however, the mechanism(s) of action still remain largely unexplained. This work investigated if irisin functions by acting as an inflammatory myokine leading to cellular stress and energy expenditure. C2C12 myotubes were treated with various concentrations of irisin, TNFα, or IL6 for various durations. Glycolytic and oxidative metabolism, as well as mitochondrial uncoupling, were quantified by measurement of acidification and oxygen consumption, respectively. Metabolic gene and protein expression were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting, respectively. Mitochondrial content was assessed by fluorescent imaging. NFκB activity was assessed using an NFκB GFP-linked reporter system. Consistent with previous findings, irisin significantly increased expression of several genes including peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) leading to increased mitochondrial content and oxygen consumption. Despite some similarities between TNFα and irisin treatment, irisin failed to activate the NFκB pathway like TNFα, suggesting that irisin may not act as an inflammatory signal. Irisin has several effects on myotube metabolism which appear to be dependent on substrate availability; however, the precise mechanism(s) by which irisin functions in skeletal muscle remain unclear. Our observations support the hypothesis that irisin does not function through inflammatory NFκB activation like other myokines (such as TNFα).

Interaction of CREB and PGC-1α Induces Fibronectin Type III Domain-Containing Protein 5 Expression in C2C12 Myotubes

“…These conflicting results might be attributed to the difference in experimental protocol or choice of anti-irisin antibodies [10]. Nevertheless, our study demonstrated that cAMP treatment increased both Fndc5 and Pgc-1α expressions in myotubes, probably because of longer stimulation (24 h) than in other in vitro models (1 h) [6,32].…”

“…Irisin is one of the most prominent metabolic myokines that is generated from contracting muscle during exercise [31]. Previous studies have demonstrated that irisin stimulation increased the metabolic rate, mitochondrial content [6,32], and FFA oxidation in myocytes [3,7]. Moreover, a positive correlation of mortality risk in acute heart failure and serum irisin was also observed, suggesting irisin can be used as a predictive biomarker for cardiovascular diseases [33].…”

Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo

“…Analysis of the mouse Fndc5 gene promoter regions predicted a VDR:RXR binding site but not RAR:RXR or PPAR:RXR binding sites [30]. Interestingly, treatment with irisin increases mitochondrial oxidative metabolism, mitochondrial uncoupling and fatty acid oxidation in skeletal muscle cells [28, 29]. Thus, irisin induction may contribute, in a paracrine/autocrine manner, to the effects of ATRA treatment on C2C12 myocyte metabolism observed in the present work.…”

“…Reported effects of the myokine irisin favoring oxidative metabolism in skeletal muscle cells [28, 29] and WAT browning [3] are reminiscent of effects triggered by ATRA treatment. This, together with the fact that the promoter of the irisin precursor gene Fndc5 contains a RXR heterodimer binding site in the mouse [30], prompted us to study the impact of ATRA treatment on the production of irisin in skeletal muscle cells.…”

WITHDRAWN: Relationship between circulating irisin, retinol binding protein-4, adiponectin and inflammatory mediators in patients with metabolic syndrome

“…The main effects of irisin are the browning of white adipose tissue and increased energy expenditure. Irisin expression and/or circulating levels have been associated with anthropometric and biochemical parameters, other hormones and adipokines, and obesity, IR, type 2 diabetes and MetS (3,4).…”