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EBioMedicine. 2019 Jul;45:251-260. doi: 10.1016/j.ebiom.2019.06.003. Epub 2019 Jun 11.

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

Author information

1
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
2
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China. Electronic address: lliu@must.edu.mo.
3
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China. Electronic address: wzma@must.edu.mo.

Abstract

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).

KEYWORDS:

Dichloroacetate; Lactate; Muscle symptoms; Statin

PMID:
31201144
DOI:
10.1016/j.ebiom.2019.06.003
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