The Effect of Low Dose Statin Combined with Grapefruit on Skeletal Muscle Structure and the Possible Protective Role of Mesenchymal Stem Cells

Abstract

Background: Statins are the cornerstone of therapy for dyslipidemia. They are generally well tolerated but can produce skeletal muscle adverse reactions, ranging from myalgia to rhabdomyolysis. Grapefruit juice increases the plasma concentrations of simvastatin thus increasing the risk of adverse effects. Stem cells have been recognized as a potential tool for the development of innovative therapeutic strategies. Objectives: To evaluate the effect of low dose statin combined with grapefruit on muscle structure and the possible protective role of Bone Marrow Mesenchymal Stem Cells (BM-MSCs) in female rats. Materials and Methods: Twenty five adult female rats were randomly divided into: Group I (control group, n=10) equally subdivided into: Subgroup IA (grapefruit control); 5 ml/kg oral grapefruit juice was given daily, Subgroup IB (statin control); 20 mg/kg oral Zocor® in tap water was given daily. Group II (statin + grapefruit, n=5); 20 mg/kg Zocor® in 5 ml/kg grapefruit juice was given daily for 45 days, Group III (IM- MSCs, n=5); statin + grapefruit were given as in Group II, in addition to two intramuscular (IM) injections of BM-MSCs. Group IV (IV- MSCs, n=5); statin + grapefruit were given as in Group II, in addition to two intravenous (IV) injections of BM-MSCs. Plasma level of Creatine Kinase (CK) was obtained at various intervals. All animals were sacrificed 12 days after the last dose, gastrocnemius muscles were collected and processed for light and electron microscopic study. Results: Both control subgroups showed unremarkable muscle changes. However, in Group II, dilated T-tubules, subsarcolemmal space widening, mitochondrial degeneration, disintegrated myofibrils, loss of Z lines and accumulation of large electron dense particles were detected. In Group III and IV these muscle changes were improved. Conclusion: Statin combined with grapefruit resulted in muscle ultrastructural changes. These changes were ameliorated with either IM and IV injection of MSCs, however IM injection showed better results.