The rate limiting step of cholesterol biosynthetic pathway is catalyzed by 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase (HGMR). Statins, HMGR inhibitors widely used against hypercholesterolemia, often cause reduced muscle performance, muscular fatigue, weakness, pain, and rarely rhabdomyolysis. Moreover, it has been recently demonstrated that HMGR inhibition is able to modulate skeletal muscle differentiation.

The aim of this work was to study the role of HMGR inhibition by simvastatin on skeletal muscle physiology. Three-month-old male rats (Rattus norvegicus) were treated for 3 weeks with a daily intraperitoneal injection of simvastatin (1.5 mg/kg/die) and biochemical, morphological, and mechanical analyses were performed on Extensor Digitorum Longus (EDL) muscle.

Our results show that EDL muscles from simvastatin-treated rats exhibited i) a reduced HMGR activity; ii) a 15% shift from the fastest myosin heavy chain (MHC) isoform IIb to the slower IIa/x; iii) a reduced power output and unloaded shortening velocity by 41% and 23% respectively, without change in isometric force and resistance to fatigue. Furthermore, in motor coordination experiments using the rotarod test, simvastatin-treated rats show a decrease in the latency to fall off the rotarod (~30%). These results indicate that the molecular mechanism of the impaired muscle function following statin treatment could be related to the plasticity of fast MHC isoform expression.