The bone anabolic effects of irisin are through preferential stimulation of aerobic glycolysis

초록

Irisin, a recently identified hormone secreted by skeletal muscle in response to exercise, exhibits anabolic effects on the skeleton primarily through the stimulation of bone formation. However, the mechanism underlying the irisin-stimulated anabolic response remains largely unknown. To uncover the underlying mechanism, we biosynthesized recombinant irisin (r-insin) using an Escherichia coll expression system and used it to treat several osteoblast cell types. Our synthesized r-irisin could promote proliferation and differentiation of osteoblasts as evidenced by enhanced expression of osteoblast-specific transcriptional factors, including Runt-related transcription factor-2 (Ruwc2), Oster (Osx), as well as early osteoblastic differentiation markers such as alkaline phosphatase (AZp) and collagen type I alpha 1 (Collal). Furthermore, we showed that the promotion of r-insin on the proliferation and differentiation of osteoblast lineage cells are preferentially through aerobic glycolysis, as indicated by the enhanced abundance of representative enzymes such as lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase 1 (PDK1), together with increased lactate levels. Suppression of r-insin-mediated aerobic glycolysis with Dichloroacetate blunted its anabolic effects. The favorite of the aerobic glycolysis after ririsin treatment was then confirmed in primary calvanal cells by metabolic analysis using gas chromatography-mass spectrometry. Thus, our results suggest that the anabolic actions of r-insin on the regulation of osteoblast lineage cells are preferentially through aerobic glycolysis, which may help to develop new irisin-based bone anabolic agents.

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