Simvastatin profoundly impairs energy metabolism in primary human muscle cells

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Mäkinen , S , Datta , N , Nguyen , Y H , Kyrylenko , P , Laakso , M & Koistinen , H A 2020 , ' Simvastatin profoundly impairs energy metabolism in primary human muscle cells ' , Endocrine Connections , vol. 9 , no. 11 , pp. 1103-1113 .

Title: Simvastatin profoundly impairs energy metabolism in primary human muscle cells
Author: Mäkinen, Selina; Datta, Neeta; Nguyen, Yen H.; Kyrylenko, Petro; Laakso, Markku; Koistinen, Heikki A.
Contributor: University of Helsinki, HUS Internal Medicine and Rehabilitation
University of Helsinki, Medicum
University of Helsinki, Minerva Foundation Institute for Medical Research
University of Helsinki, HUS Internal Medicine and Rehabilitation
Date: 2020-11
Language: eng
Number of pages: 11
Belongs to series: Endocrine Connections
ISSN: 2049-3614
Abstract: Objectives: Simvastatin use is associated with muscular side effects, and increased risk for type 2 diabetes (T2D). In clinical use, simvastatin is administered in inactive lipophilic lactone-form, which is then converted to active acid-form in the body. Here, we have investigated if lactone- and acid-form simvastatin differentially affect glucose metabolism and mitochondrial respiration in primary human skeletal muscle cells. Methods: Muscle cells were exposed separately to lactone- and acid-form simvastatin for 48 h. After pre-exposure, glucose uptake and glycogen synthesis were measured using radioactive tracers; insulin signalling was detected with Western blotting; and glycolysis, mitochondrial oxygen consumption and ATP production were measured with Seahorse XF(e)96 analyzer. Results: Lactone-form simvastatin increased glucose uptake and glycogen synthesis, whereas acid-form simvastatin did not affect glucose uptake and decreased glycogen synthesis. Phosphorylation of insulin signalling targets Akt substrate 160 kDa (AS160) and glycogen synthase kinase 3 beta (GSK3 beta) was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production. Conclusions: These data suggest that lactone- and acid-forms of simvastatin exhibit differential effects on non-oxidative glucose metabolism as lacto ne-form increases and acid-form impairs glucose storage into glycogen, suggesting impaired insulin sensitivity in response to acid-form simvastatin. Both forms profoundly impair oxidative glucose metabolism and energy production in human skeletal muscle cells. These effects may contribute to muscular side effects and risk for T2D observed with simvastatin use.
Subject: ATP production
glucose uptake
glycogen synthesis
HMG-CoA reductase inhibitor
insulin resistance
mitochondrial respiration
skeletal muscle
3121 General medicine, internal medicine and other clinical medicine

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