HDAC5 regulates IL-6 transcription and enhances insulin signaling in skeletal muscle

Background and aims:

Muscle derived IL-6 secretion following exercise has been linked to improvements of insulin sensitivity and maintenance of glucose hemostasis via its endocrine, autocrine and paracrine roles. Recently, it has been reported that histone acetylation can regulate transcription of IL-6 but its involvement in muscle derived IL-6 was not completely known. Exercise mediated changes have been reported to inhibit HDAC5, a class IIa histone deacetylase. In this study, we analyzed the role of HDAC5 in IL-6 transcription and glucose hemostasis in muscle following exercise stimulation.

Methods:

We analyzed HDAC5 knockout mice (KO) and controls (WT) on a C57BL/6J background, and a HDAC5 knockdown (KD) C2C12 cell line. Chromatin immunoprecipitation studies were performed to analyze IL-6 promoter analysis using H3K9ac and HDAC5 antibodies.

Results:

Microarray analysis of HDAC5 KO gastrocnemius muscle showed activation of the IL-6 pathway. Most importantly, we found that knockdown of HDAC5 in C2C12 leads to higher expression and secretion of IL-6 with enhanced insulin-stimulated activation of AKT which was reversed by IL-6 knockdown. As a result, HDAC5 KD myotubes showed enhanced glucose uptake and GLUT4 expression. Transcription of IL-6 was further enhanced by electrical pulse stimulation in HDAC5 KD C2C12 cells. HDAC5 showed positive association with the IL-6 promoter and activation of histone H3K9ac marks in HDAC5 KD C2C12 cells. Finally, exercise intervention to HDAC5 KO mice showed improved glucose tolerance as compare to WT mice.

Conclusion:

HDAC5 epigenetically regulates IL-6 transcription and synergistically enhances insulin signaling in skeletal muscle.