Study of the role of products and enzymes of cholesterol biosynthetic pathway in muscle tissues

Abstract

Mevalonate pathway is an important metabolic pathway providing cells with vital bioactive compounds such as cholesterol, prenyls, ubiquinone and dolichol. All of them play pivotal roles in muscle structure and functions being involved in ATP production, contractile regulation and myoblast fusion into multinucleated syncitia. The key and rate limiting step of the pathway is the reduction of 3-hydroxy-3-methylglutaryl Coenzyme A in mevalonate, reaction catalized by the enzyme 3-hydroxy-3-methylglutaryl Coenzyme A reductase (HMGR) that as a central regulator of cholesterol homeostasis is highly regulated. Statins, drugs widely used in ipocholesterolemic therapies, competitively inhibit HMGR: besides the well known lipid lowering properties they can also exert muscle side effects with symptoms ranging from weakness and pain to symptoms associated to rabdhomyolysis, a life threatening condition. The majority of the studies so far are limited to the definition of statin-induced myotoxicity omitting to investigate whether and how HMGR inhibition can affect muscle physiology. The PhD project was aimed at providing a comprehensive analysis of the role played by HMGR and its main end-products in skeletal muscle development, repair and functionality and in cardiac muscle structure and metabolism. The thesis provides evidence that HMGR inhibition negatively affects myoblast differentiation and fusion, delays muscle regeneration, impairs the mechanical and functional features of glycolytic fibers, leads to changes in cardiac fiber phenotype. Thus, statin users might not only suffer from myopathy but also might not be able to repair any muscle damage. Furthermore, even though statins are supposed to reduce the risk of cardiovascular disease, they can also affect energy-dependent myocardial functions. In conclusion the results suggest that more efforts should be spent to find alternative pharmacological approach to statin treatment, able to block cholesterol biosynthetic pathway downstream to HMGR, the inhibition of which can affect body health at multiple levels.