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Myotoxic reactions to lipid-lowering therapy are associated with altered oxidation of fatty acids

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Abstract

Despite exceptional efficacy and safety, fear of muscle toxicity remains a major reason statins are underutilized. Evidence suggests that statin muscle toxicity may be mediated by abnormalities in lipid metabolism. To test the hypothesis that myotubes from patients intolerant of lipid-lowering therapies have abnormal fatty acid oxidation (FAO) responses we compared muscle from 11 subjects with statin intolerance (Intolerant) with muscle from seven statin-naive volunteers undergoing knee arthroplasty (Comparator). Gross muscle pathology was graded and skeletal muscle cell cultures were produced from each subject. FAO was assessed following treatment with increasing statin concentrations. There was no difference in muscle biopsy myopathy scores between the groups. Basal octanoate oxidation was greater in Intolerant than in Comparator subjects (P = 0.03). Lovastatin-stimulated palmitate oxidation tended to be greater for Intolerant compared to Control subjects’ myotubes (P = 0.07 for 5 μM and P = 0.06 for 20 μM lovastatin). In conclusion abnormalities in FAO of Intolerant subjects appear to be an intrinsic characteristic of these subjects that can be measured in their cultured myotubes.

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Abbreviations

AT:

Anaerobic threshold

BSA:

Bovine serum albumin

CK:

Creatine kinase

CPT:

Carnitine palmityl transferase

CPX:

Cardiopulmonary exercise testing

FAO:

Fatty acid oxidation

FFA:

Free fatty acid

IOA:

Index of abnormality pathology score

MI:

Metabolic index pathology score

PPAR:

Peroxisome proliferator-activated receptor

RER:

Respiratory exchange ratio

VO2 max :

Maximal oxygen consumption

VE/VCO2 :

Ventilatory efficiency

TSH:

Thyroid stimulating hormone

BMI:

Body mass index

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Acknowledgments

We would like to acknowledge the efforts of research nurses Nancy L. Gray and Lynda M. Puhek and exercise technician Frederich G. McDonald in collecting patient information, and of Mickey Robinson for citation assistance. This work was supported in part by the Skaggs Clinical Scholars Program of The Scripps Research Institute (PSP), a grant from the Medical Research Service, Department of Veterans Affairs and VA San Diego Healthcare System (RRH), grants from the American Diabetes Association (TPC, RRH), and grant M01 RR-00827 in support of the General Clinical Research Center from the General Clinical Research Branch, Division of Research Sources, NIH (TPC, RRH). The Scripps Clinical Research Center is a voluntary, collaborative clinical research group including: Richard Blum, MD, Thomas E Diggs, MD, Stewart Frank, MD, Richard Friedman, MD, Jerrold G Glassman, MD, Nancy L. Gray, RN, Stephen Gross, MD, Shahine Keramati, MD, Bruce J. Kimura, MD, Christopher Malloch, MD, John Mazur, MD, Douglas Mooney, MD, John Morse, MD, Jeffrey Mullvain, MD, Paul S. Phillips, MD, Lynda M. Puhek, RN, Ali Salami, MD, Emily Scott, MD, Harminder Sikand, Pharm D, Michael Sullivan, MD, David Shaw, MD, Joseph Stein, MD, David Stieber, MD, and Jeffrey Williams, MD.

Conflict of interest statement

P. S. Phillips has received honoraria, consulting fees or research funding from Pfizer, Merck, Schering Plough, and Sankyo.

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Authors and Affiliations

  1. Cardiology Catheterization Laboratories (Mer 74), Scripps Mercy Clinical Research Center, Scripps Mercy Hospital, 4077 Fifth Ave, San Diego, CA, 92103, USA

    Paul S. Phillips

  2. VA San Diego Healthcare System, San Diego, CA, 92161, USA

    Theodore P. Ciaraldi, Dong-Lim Kim & Robert R. Henry

  3. Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA

    Theodore P. Ciaraldi, Dong-Lim Kim & Robert R. Henry

  4. Department of Internal Medicine, College of Medicine, Konkuk University, Seoul, South Korea

    Dong-Lim Kim

  5. Neuropathology Laboratory, University of California, Los Angeles, CA, USA

    M. Anthony Verity

  6. Division of Biostatistics and Bioinformatics in Family and Preventive Medicine, University of California, San Diego, La Jolla, CA, 92093, USA

    Tanya Wolfson

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  1. Paul S. Phillips
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Correspondence to Paul S. Phillips.

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Phillips, P.S., Ciaraldi, T.P., Kim, DL. et al. Myotoxic reactions to lipid-lowering therapy are associated with altered oxidation of fatty acids. Endocr 35, 38–46 (2009). https://doi.org/10.1007/s12020-008-9126-2

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  • DOI: https://doi.org/10.1007/s12020-008-9126-2

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