Fndc5/irisin is regulated by myogenesis stage, irisin, muscle type and training

Objectives: Irisin, a novel myokine that responds to exercise, was initially identified as a regulator of fat tissue metabolism. We aimed to investigate fibronectin type III domain-containing protein 5 (Fndc5)/irisin, auto/ para-crine role in different muscle fibers, different activities, and muscle cell differentiation. Methods: Using in-vitro, ex-vivo, and in-vivo muscle models, Fndc5 was studied at the physiological and molecular levels. Results: Following training, C57BL/6 mice (n=10) were subject to fast and slow-twitch muscles dissection and molecular analysis. Isolated mice (C57BL/6, n=14) slow and fast-twitch muscles were subject to electrical aerobic and anaerobic pulses stimulation (EPS). L6 muscle cells differentiation was characterized by Fndc5 differentiation-depended expression pattern parallel with significant hypertrophy, Myogenin elevation, and overlapping Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (Pgc-1 alpha) expression pattern. Exogenous irisin significantly altered Fndc5 ex-pression; augmented at early differentiation (3-4-fold, P < 0.05) and decreased (2-fold, P < 0.05) at late differen-tiation. Training induced a significant elevation in Fndc5/irisin and Pgc-1 alpha expression levels in all muscle types compared to the sedentary state, where soleus muscle (slow) Fndc5 expression levels were significantly higher compared to levels in all other fast muscles (3-140-fold, P < 0.001). Similarly, following EPS, Fndc5 expression levels were significantly augmented in the soleus slow muscle following both aerobic and anaerobic activity (3-3.5-fold, P < 0.05) compared to extensor digitorum longus (fast) muscle. Conclusions: Muscle cell's Fndc5 expression has a differentiation-depended pattern paralleling Pgc-1 alpha expression and hypertrophy. Irisin autocrinally and significantly regulate Fndc5 and Pgc-1 alpha in a differentiation-depended manner. Muscle Fndc5 expression levels are dependent on fiber type and activity type.