Applying exercise-mimetic engineered skeletal muscle model to interrogate the adaptive response of irisin to mechanical force

Physical exercise induces the secretion of irisin from contractile muscle into circulation; however, the adaptive response of irisin to mechanical stimulus in skeletal muscle in vitro remains numerously unknown. In an effort to investigate whether irisin is inducible in vitro, we developed a bioreactor consisting of a retractable mechanical force controller and a conditional tissue culture system. Upon this model, a distinguished surge of irisin was detected in stretched myotubes as cyclic strain initiated, and the surge was able to be stalled by knocking out FNDC5. Intriguingly, increased irisin secretory is associated with the shifts of MyHC isoforms from anaerobic type to aerobic type in myotubes. We further revealed that PGC-1α1 and PGC-1α4 mRNAs expression, rather than PGC-1α2 and PGC-1α3, contributed to the generation of irisin in myotubes during cyclic strain. Lastly, combined with co-culturing MC3T3 osteoblasts, we demonstrated the bioactivity of generated irisin, promoting the osteogenic differentiation.