The effect of low dose statin combined with grapefruit on muscle structure and the possible protective role of mesenchymal stem cells

Abstract

Background and objectives: Statins are the cornerstone of therapy for dyslipidemia. They are generally well tolerated but can produce a variety of skeletal muscle adverse reactions, ranging from muscle pain to frank rhabdomyolysis. Grapefruit juice increases the plasma concentrations of simvastatin thus increasing both the cholesterol-lowering effect and the risk of adverse effects. Stem cells have been recognized as a potential tool for the development of innovative therapeutic strategies. This study was conducted to evaluate the effect of low dose statin combined with grapefruit ingestion on muscle structure and the possible protective role of bone marrow mesenchymal stem cells (BM-MSCs) in female rats. Materials and methods: Thirty adult female rats were divided into two groups. Group I: control group (n=12) equally subdivided into two subgroups. Subgroup IA (grapefriut control); oral grapefruit juice was given daily in a dose of 5mg/kg, Subgroup IB (statin control); oral Zocor® was given daily in a dose of 20mg/kg suspended in tap water. Group II: Experimental group (18 rats) in which 20 mg/kg Zocor® suspended in 5mg/kg grapefruit juice was given daily. This group was subdivided randomly into subgroup IIA (statin + grapefruit) in which the previous dose was given for 45 days, Subgroup IIB (IM- MSCs) in which two intramuscular (IM) injections of BM-MSCs was given, Subgroup IIC (IV- MSCs) in which two intravenous (IV) injections of BM-MSCs was given in days3 and 33 of the experiment. Plasma level of creatinine kinase was obtained at various intervals. All animals were sacrificed after 12 days from last injection and gastrocnemius muscle samples were collected and processed for light and electron microscopic study. Results: Both control subgroups showed unremarkable muscle changes. However, in subgroup IIA, loss of muscle striations in some fibers, increased nuclear number, subsarcolemmal mitochondrial changes, separation of myofibrils, affection of some sarcomeres with loss of Z lines and prominent t-tubules as well as increased collagen and glycogen were detected. In subgroups IIB and IIC these muscle changes were ameliorated. Conclusion: Low dose statin combined with grapefruit resulted in muscle structure changes. These changes were ameliorated with either IM and IV injection of MSCs, however IM injection showed better results.