Abnormal glucose metabolism and muscle mass decline by bisphenol A or bisphenol S in skeletal muscle of male mice:inhibition of mitophagy by downregulation of the ERα/AMPK/ULK1 pathway.

The comorbidity of type 2 diabetes mellitus (T2DM) and sarcopenia is becoming increasingly prominent. Studies have shown that bisphenol A (BPA) or bisphenol S (BPS) exposure increases the risk of T2DM. However, the mechanisms by which BPA or BPS affect skeletal muscle glucose metabolism had remained limited and few investigations have addressed their impacts on skeletal muscle mass. In this study, male mice were administered 50 μg/kg bw/d BPA or BPS via drinking water for 16 weeks. Our results demonstrated that BPA or BPS exposure increased FBG and GHbA1c levels while reducing muscle glycogen content, which were attributed to the inhibition of insulin signaling in skeletal muscle. BPA or BPS exposure impaired motor function and skeletal muscle fiber structure, and disrupted the balance of myocyte apoptosis and differentiation, manifested by increased expression of apoptosis-related proteins and Mstn, while downregulating Myog and Myod. Mitochondrial damage and oxidative stress were observed in both BPA and BPS groups. BPA or BPS exposure impaired mitophagy, as indicated by increased levels of LC3B, p62, TOM20 and COXIV, as well as decreased PINK1 and Parkin expression. Moreover, the ERα/AMPK/ULK1 pathway was inhibited in the BPA and BPS groups. Our results revealed that BPA or BPS exposure could impair glucose metabolism and reduce muscle mass, which might be associated with abnormal mitophagy induced by the downregulation of the ERα/AMPK/ULK1 pathway.