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

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 ?-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/?-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).

SUBMITTER: Huang J

PROVIDER: S-EPMC6642070 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Huang Jiajun J Du Jingjing J Lin Wanjun W Long Ze Z Zhang Na N Huang Xiaoming X Xie Ying Y Liu Liang L Ma Wenzhe W

EBioMedicine 20190611

<h4>Background</h4>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.<h4>Methods</h4>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 experim ...[more]

PMID: 31201144

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Project description:Lactate, traditionally considered a metabolic by-product, has recently been identified as a substrate for the induction of lactylation, a newly identified epigenetic modification that plays an important role in the regulation of host gene expression. Our previous study showed that lactate levels were significantly elevated in cells infected with the porcine reproductive and respiratory syndrome virus (PRRSV), an Arterivirus that has devastated the swine industry worldwide for over 30 years. However, the role of elevated lactate in PRRSV infections remains unknown. In this study, we found that lactate was required for optimal PRRSV proliferation, and PRRSV infection increased cellular lactylation in a dose-dependent manner. Using the Cleavage Under Targets and Tagmentation (CUT&Tag) combined with RNA sequencing (RNA-seq) to screen the downstream genes regulated by lactylation in PRRSV-infected cells, we found that PRRSV-induced lactylation activated the expression of heat shock 70 kDa protein 6 (HSPA6). Follow-up experiments showed that HSPA6 is important for PRRSV proliferation by negatively modulating interferon (IFN)-β induction. Mechanistically, HSPA6 impeded the interaction between TNF-receptor-associated factor 3 (TRAF3) and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), thereby hindering the production of IFN-β. Taken together, these results indicate that the activated lactate-lactylation-HSPA6 axis promotes viral growth by impairing IFN-β induction, providing new therapeutic targets for the prevention and control of PRRSV infection. The results presented here also link lactylation to the virus life cycle, improving our understanding of epigenetic regulation in viral infection.IMPORTANCEAs a newly identified epigenetic modification, lactate-induced lactylation has received attentions because it plays important roles in gene expression and contributes to tumorigenesis and the innate immune response. Previous studies showed that many viruses upregulate cellular lactate levels; however, whether virus-elevated lactate induces lactylation and the subsequent biological significance of the modification to viral infection have not been reported. In this study, we demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) infection induced cellular lactylation, which, in turn, upregulated the expression of HSPA6, an IFN-negative regulator. We also dissected the mechanism by which HSPA6 negatively regulates IFN-β production. To our knowledge, this is the first report to study virus-induced lactylation and establish the relationship between lactylation and virus infection.

Project description:UnlabelledPatients with familial hypercholesterolemia (FH) may be at increased risk for statin-associated muscle symptoms because they require long-term treatment with high-intensity statin therapy. We sought to determine (1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms-solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056-also increase the risk of statin-associated muscle symptoms in FH patients, and (2) the natural history and management for FH patients with statin-associated muscle symptoms.MethodsWe queried electronic records (2004-2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment low-density lipoprotein cholesterol [LDL-C] 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX, area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy.ResultsThe risk of muscle symptoms was associated with age (odds ratio 1.6 [95% CI 1.2-2.2]), body mass index in non-African Americans (0.90 [0.83-0.97]), and hypertension (0.4 [0.2-0.9]). Simvastatin was the most commonly used statin, and it was the statin most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy ("eventually tolerant") and 29% (n = 28) never reestablished statin therapy ("never tolerant"). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually tolerated statins, and eventually tolerant patients achieved lower treated LDL-C levels (eventually tolerant 127 vs never tolerant 192 mg/dL, P < .001). Never tolerant patients also developed muscle symptoms on nonstatins (16% vs 50%, P = .003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (odds ratio 1.40 [95% CI 0.74-2.64]).ConclusionAge, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never reestablished statin therapy. Such patients developed muscle symptoms even on nonstatin lipid-lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship between FH and statin-associated muscle symptoms so all FH patients can be adequately treated.

Project description:IntroductionStatin-associated muscle symptoms (SAMSs) are a major clinical issue in the primary and secondary prevention of cardiovascular events. Current guidelines advise various approaches mainly based on expert opinion. We will lead a systematic review and meta-analysis to explore the tolerability and acceptability and effectiveness of statin-based therapy management of patients with a history of SAMS. We aim to provide evidence on the tolerability and different strategies of statin-based management of patients with a history of SAMS.Methods and analysisWe will conduct a systematic review of randomised controlled trials (RCTs) and non-randomised studies with a control group. We will search in Data sources MEDLINE, EMBASE, Cochrane Central Register of Controlled Clinical Trials, Scopus, Clinicaltrials.gov and Proquest from inception until April 2021. Two independent reviewers will carry out the study selection based on eligibility criteria. We will extract data following a standard data collection form. The reviewers will use the Cochrane Collaboration's tools and Newcastle-Ottawa Scale to appraise the study risk of bias. Our primary outcome will be tolerability and our secondary outcomes will be acceptability and effectiveness. We will conduct a qualitative analysis of all included studies. In addition, if sufficient and homogeneous data are available, we will conduct quantitative analysis. We will synthesise dichotomous data using OR with 95% CI and continuous outcomes by using mean difference or standardised mean difference (with 95% CI). We will determine heterogeneity visually with forest plots and quantitatively with I2 and Q-test. We will summarise the confidence in the quantitative estimate by using Grading of Recommendations Assessment, Development and Evaluation approach.Ethics and disseminationAs a systematic review of literature without collection of new clinical data, there will be no requirement for ethical approval. We will disseminate findings through peer-reviewed publications.Prospero registration numberCRD42020202619.

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

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

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