Benzo[a]pyrene inhibits myoblast differentiation through downregulating the Hsp70-MK2-p38MAPK complex

Abstract

Cigarette smoking causes skeletal muscle dysfunction and worse prognosis for patients with diverse systemic diseases. Benzo[a]pyrene (BaP), one major constituent that is inhaled during smoking, is particularly known for its ability to impair neurodevelopment, impede reproductivity, or reduce birth weight. Here, we found that BaP exposure led to the inhibition of C2C12 myoblasts differentiation in a dose-dependent manner and reduced the expression of both early and late myogenic differentiation markers. BaP exposure significantly decreased the expression of p38 mitogen-activated protein kinase (p38MAPK), but not AKT, which are both critical during myogenic differentiation. Mechanistically, BaP downregulated the expression levels of MAPK-activated protein kinase 2 (MK2) and heat shock protein 70 (Hsp70), both of which stabilize p38MAPK. Interestingly, treatment of proteasome inhibitor MG132 was able to reverse BaP-induced degradation of Hsp70/ MK2 and p38MAPK in myoblasts, implying BaP-mediated p38MAPK degradation is proteasome-dependent. Overexpression of p38MAPK also rescued the defective differentiation phenotype of C2C12 induced by BaP. Taken together, we suggest that BaP exposure induces MK2/Hsp70/p38MAPK complex degradation in C2C12 myoblasts and impairs myogenic differentiation by proteasomal-dependent mechanisms. As application of the proteasome inhibitor MG132 or overexpression of p38MAPK could reverse impaired differentiation of myoblasts induced by BaP, this may suggest potential related strategies for preventing tobacco-related skeletal muscle diseases or for respiratory rehabilitation.