Statin-Induced Myopathy: Translational Studies from Preclinical to Clinical Evidence

Abstract

Statins are the most prescribed and effective drugs to treat cardiovascular diseases (CVD). Nevertheless, these drugs can be responsible for skeletal muscle toxicity which leads to reduced compliance. The discontinuation of therapy increases the incidence of CVD. Thus, it is essential to assess the risk. In fact, many studies have been performed at preclinical and clinical level to investigate pathophysiological mechanisms and clinical implications of statin myotoxicity. Consequently, new toxicological aspects and new biomarkers have arisen. Indeed, these drugs may affect gene transcription and ion transport and contribute to muscle function impairment. Identifying a marker of toxicity is important to prevent or to cure statin induced myopathy while assuring the right therapy for hypercholesterolemia and counteracting CVD. In this review we focused on the mechanisms of muscle damage discovered in preclinical and clinical studies and highlighted the pathological situations in which statin therapy should be avoided. In this context, preventive or substitutive therapies should also be evaluated.

Management of Hypercholesterolemia Through Dietary ß-glucans–Insights From a Zebrafish Model

“…Based on our results, dietary simvastatin suppressed translation, rRNA modification, rRNA metabolic process and peptide biosynthetic process indicating an impact of the product on the protein synthesis machinery of the intestine. Statin-induced depletion of cholesterol in the striated muscle cells destabilizes membrane potential and alters ion balance in the cells thus affecting protein synthesis ( 88 ). Suppression of cholesterol biosynthesis by statins also leads to the deficiency of intermediates like farnesyl pyrophosphate and ubiquinone which are generated during cholesterol biosynthesis.…”

Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes

“…However, when we exercised 1 mM fluvastatin-treated flies in the Forced-Climbing System for six hours, the number of ClC-a gold particles was not altered in comparison with the control group (Supplementary Figure S5A), suggesting that the exercise improves the expression of the ClC-a in the skeletal muscles. Consistent with this is the observation that the muscle biopsy from patients and rats treated with fluvastatin exhibit manifestations of myopathy in which the skeletal muscles show lowered ClC-1 protein expression and decreased chloride conductance with no change in ClCN1 transcript levels [44][45][46]. Additionally, in humans, moderate exercise has been shown to improve the manifestation of SIM, although the data are conflicting [72,131,132].…”

“…Apart from the mevalonate pathway, a reduction in insulin secretion and sensitivity by statins has been also proposed as an underlying factor for SIM [ 40 , 41 , 42 ]. It has been also reported that statin treatment is associated with the inhibition of skeletal muscle chloride channel 1, CLC-1 [ 43 , 44 , 45 , 46 ], which is the key feature of myotonia [ 47 , 48 ]. Nevertheless, whether statin-associated inhibition of CLC-1 can cause myopathy phenotypes and the mechanistic pathway underlying statin-associated inhibition of CLC-1 are still poorly understood.…”

Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy

“…A 2019 followup study of the same group demonstrated that simvastatin markedly improves cardiac functions in the dystrophic mdx mouse, and therefore may provide a novel approach for treating cardiomyopathy in DMD [12]. In the general population, however, the use of statin is well known to be associated with a risk for the development of deleterious muscle side-effects [13]. This makes the use of statin contra-intuitive, in the context of muscular dystrophy.…”

“…In this context, the attempts to reproduce these promising results by other independent laboratories had failed, since the treated mdx mice did not present muscle functional improvement [14,15]. These negative results are explained possibly by the relatively low level of simvastatin that was measured in the treated mice [16], yet, the failure to validate the early results, associated with the statins' notorious propensity to cause muscle pain in the general population [13], raised doubt on the therapeutic hopes of simvastatin administration in DMD.…”