Key genes and processes affected by atorvastatin treatment in mouse diaphragm muscle

Abstract

Statins are one of the top prescribed medications and are used for preventing or treating cardiovascular diseases. Myalgia, muscle fatigue, weakness, and inflammation are the most common side effects of these drugs collectively named statin-associated muscle symptoms (SAMS). The mechanisms underlying SAMS remain unclear. Given that statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of mevalonate pathway, responsible for synthesis of cholesterol and other vital molecules, SAMS may be mediated by multiple reasons. Herein, using unbiased whole transcriptome sequencing, we identified statin-affected processes and then assessed them using fluorescent, biochemical, and histological approaches in the mouse diaphragm, the main respiratory muscle. Mice were orally treated for 1 month with atorvastatin, the most prescribed statin, at clinically relevant dose. We found that atorvastatin caused downregulation of genes encoding proteins required for oxidative phosphorylation and anabolic processes, whereas genes of proteins engaged inflammation and muscle atrophy were mainly up-regulated. Furthermore, alterations in gene expression pattern suggest oxidative stress and abnormal lipid accumulation. This transcriptome signature correlated to a decrease in mitochondrial polarization and protein synthesis capacity, as well as an increase in lipid peroxidation and reactive oxygen species production. In addition, atorvastatin treatment caused lipid raft disruption, phospholipidosis, myelin de-compactization, and appearance of greater heterogeneity of muscle fiber cross-section diameter. Thus, atorvastatin treatment can negatively affect diaphragm muscle via oxidative stress accompanied by decrease in mitochondrial activity, protein synthesis, and stability of plasma membrane. As a part of compensatory response can serve enhanced activity of superoxide dismutase and cholesterol uptake capacity.

Keywords: Cholesterol; Mitochondria; Oxidative stress; Skeletal muscle atrophy; Statin.