Regulation of lactate production through p53/β-enolase axis contributes to statin-associated muscle symptoms.

BACKGROUND

Statin-associated muscle symptoms (SAMS) are the major adverse effects of the class of widely used lipid-lowering agents, and the underlying mechanism remains elusive. In this study, we investigated the potential contribution and molecular mechanism of increased lactate production to SAMS in mice.

METHODS

C57BL/6 J mice were administrated with lovastatin and exercise capacity and blood and muscle lactate levels were measured. A variety of metabolic and molecular experiments were carried out on skeletal muscle cell lines A-204 and C2C12 to confirm the in vivo findings, and to delineate the molecular pathway regulating lactate production by statins.

FINDINGS

Blood lactate levels of mice treated with lovastatin increased 23% compared to the control group, which was reproduced in type II predominant glycolytic muscles, accompanied with a 23.1% decrease of maximum swim duration time. The in vitro evidence revealed that statins increased the expression of muscle specific glycolytic enzyme β-enolase through promoting the degradation of basal p53 proteins, resulting in increased of lactate production. Co-administered with dichloroacetate (DCA), a reagent effective in treating lactic acidosis, reverted the elevated lactate levels and the decreased exercise capacity.

INTERPRETATION

Elevated lactate production by statins through the p53/β-enolase axis contributes to SAMS. FUND: This work was supported by grants from the Science and Technology Development Fund (FDCT) of Macau (Project codes: 034/2015/A1 and 0013/2019/A1).