Aim: 

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) represents the key enzyme which catalyses the rate limiting reaction of the cholesterol biosynthetic pathway, producing mevalonate (MVA) and is involved in cellular processes such as proliferation and differentiation. Statins are able to block enzyme activity and are used in hypocholesterolemic protocols even if muscle side-effects are detectable. So, the molecular mechanisms underlying the role of HMG-CoAR during muscle differentiation have been investigated to get insights on of the statin side-effects and to provide basis for new therapeutic strategies in muscle degenerative diseases.

Methods: 

Rat L6 myoblasts were treated with insulin to induce differentiation; myogenic process has been checked by Myogenin and Myosin Heavy Chain appearance along with immunocytochemical analysis. Protein levels were measured by western blotting.

Results: 

During myogenesis, HMG-CoAR activity as well as its end-products (cholesterol and prenylated proteins) is strongly modulated and its importance is demonstrated by the prevention of the insulin-induced L6 differentiation after the inhibition of HMG-CoAR activity. Insulin is able to activate p38/MAPK signal transduction pathway and the inhibition of this pathway prevents both HMG-CoAR modulation and muscle differentiation.

Conclusion: 

Our data show that HMG-CoAR is strictly related to L6 differentiation by the production of prenylated proteins and the activation of p38/MAPK signal transduction pathway.

The presented data could help to explain the process responsible of the statin-induced myopathy and could provide the basis of new drug targets for muscle degenerative disease.