Simvastatin profoundly impairs energy metabolism in primary human muscle cells

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 XFe96 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 3β (GSK3β) 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 lactone-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.

Finnish-specific AKT2 gene variant leads to impaired insulin signalling in myotubes

“…Primary muscle cell cultures were established from vastuslateralis muscle biopsies ( Skrobuk et al 2012 , Mäkinen et al 2020 ). Myoblasts were differentiated into multinucleated myotubes for 6–7 days in low glucose (5.6 mmol/L) DMEM/F12 containing 2% (v/v) FBS.…”

“…Intracellular signalling targets were investigated in differentiated myotubes with Western blotting ( Skrobuk et al 2012 , Mäkinen et al 2020 ), by detecting the phosphorylated and corresponding total proteins with antibodies, which were visualized by enhanced chemiluminescence and quantified using Fiji software ( Schindelin et al 2012 ) (for signalling targets AKT, AS160 and GSK3β) or Image Lab software (Bio-Rad) (for signalling targets MNK2, eIF4E and FAK) ( Supplementary Material ). Unless otherwise noted, intensities of the phosphorylated proteins were normalized to the intensity of their corresponding total protein and data were normalized to the basal control sample of each subject.…”

Literature Review of Atherosclerosis Treatment with Hibiscus Sabdariffa as an Alternative for Statin Therapy

“…Sambubioside) [15]. Additionally, qualitative analysis has been utilized through the Thin Layer Chromatographic technique, reporting that each leaf, seed, flower, and root of HS contains the primary and secondary metabolites in the form of alkaloids and flavonoids phenolics, saponins, and glycosides [16].…”

“…In addition, several studies have reported that phenolic compounds are the most abundant compounds contained in HS. Particularly, flavonoids are regarded as one of the most abundant phenolic compounds in all parts of HS, acting as antioxidant agents [14,16]. Flavonoids are also beneficial in lowering oxysterols (cholesterol derivatives) in bile acid metabolism, blocking fat accumulation in the liver.…”

Role of Lactone and Acid Forms in the Pleiotropic Effects of Statins

“…This novel therapeutic approach, based on the regulation of membrane lipid structure, is referred as Membrane Lipid Therapy, and is evolving rapidly due to its potential use in the treatment of several human disorders [10]. The contemporary use of both acid and lactone form of statins is an increasingly common strategy in scientific studies, and can contribute to a better understanding of the mechanisms behind statin uptake, metabolism and occurrence of pleiotropic effects [11,12] (Figure 1).…”