Free Fatty Acid Impairs Myogenic Differentiation through the AMPKα-MicroRNA 206 Pathway

ABSTRACT

The activity of AMP-activated protein kinase α (AMPKα) is reduced in type 2 diabetes, and type 2 diabetes is associated with muscular atrophy. To date, there is little known about the mechanism by which free fatty acid (FFA) participates in muscular impairment. The purpose of the present study was to explore whether FFA damages myogenesis through the AMPKα-histone deacetylase 4 (HDAC4)-microRNA 206 (miR-206) pathway. The results showed that 1 mM FFA produced lipid accumulation, significantly impaired the insulin signaling pathway, and decreased the myogenic differentiation of C2C12 myoblast cells. FFA reduced the LKB1-AMPKα pathway, and the activation of AMPKα rescued the myogenic impairment caused by FFA (P < 0.05). AMPKα promoted myogenesis by regulating the expression of miR-206 through HDAC4 (P < 0.05) and affected the cell cycle and cell proliferation to promote myogenesis by regulating miR-206 and miR-206’s target cyclin D1 gene. In addition, AICAR (5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside) and HDAC4 small interfering RNA (siRNA) promoted myogenic differentiation compared with the FFA group; however, this positive effect was significantly downregulated after transfection with the miR-206 inhibitor. In summary, AMPKα plays positive roles in myogenic differentiation and myogenesis, and FFA decreased myogenic differentiation and myotube formation through the AMPKα–HDAC4–miR-206 pathway.

KEYWORDS:

• AMPKα
• miR-206
• cell cycle
• FFA
• myogenic differentiation

ACKNOWLEDGMENTS

This work was supported by Breeding and Reproduction in The Major Agricultural Plan of New Variety Innovation of Jiangsu Province (PZCZ201734), the Natural Science Foundation of Jiangsu Province (BK20130693), and The National Major Project of Breeding for Transgenic Pigs (2016ZX08006001-003).

We have no conflict of interest to declare.

Funding acquisition, Wangjun Wu and Honglin Liu; Investigation, Aiwen Jiang and Wangjun Wu; Methodology, Liangliang Zhang and Xiaoyu Jiang; Project administration, Wangjun Wu; Visualization, Xiying Zhang; Writing – original draft, Aiwen Jiang and Hongyun Guo; Writing – review & editing, Honglin Liu.