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-1α) expression pattern. Exogenous irisin significantly altered Fndc5 expression; augmented at early differentiation (3-4-fold, P<0.05) and decreased (2-fold, P<0.05) at late differentiation. Training induced a significant elevation in Fndc5/irisin and Pgc-1α 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-1α expression and hypertrophy. Irisin autocrinally and significantly regulate Fndc5 and Pgc-1α in a differentiation-depended manner. Muscle Fndc5 expression levels are dependent on fiber type and activity type.