title: 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibition impairs muscle regeneration.
abstract: Skeletal muscle has the ability to regenerate new muscle fibers after injury. The process of new muscle formation requires that quiescent mononuclear muscle precursor cells (myoblasts) become activated, proliferate, differentiate, and fuse into multinucleated myotubes which, in turn, undergo further differentiation and mature to form functional muscle fibers. Previous data demonstrated the crucial role played by 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGR), the rate-limiting enzyme of cholesterol biosynthetic pathway, in fetal rat myoblast (L6) differentiation. This finding, along with epidemiological studies assessing the myotoxic effect of statins, HMGR inhibitors, allowed us to speculate that HMGR could be strongly involved in skeletal muscle repair. Thus, our research was aimed at evaluating such involvement: in vitro and in vivo experiments were performed on both mouse adult satellite cell derived myoblasts (SCDM) and mouse muscles injured with cardiotoxin. Results demonstrate that HMGR inhibition by the statin Simvastatin reduces SCDM fusion index, fast MHC protein levels by 60% and slow MHC by 40%. Most importantly, HMGR inhibition delays skeletal muscle regeneration in vivo. Thus, besides complaining of myopathies, patients given Simvastatin could also undergo an impairment in muscle repair.
authors.affiliation: Department of Biology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Trapani
authors.forename: Marco
authors.initials: M
authors.lastname: Segatto
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: La Rosa
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanelli
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.forename: Maria
authors.initials: M
authors.lastname: Marino
authors.forename: Valentina
authors.initials: V
authors.lastname: Pallottini
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology*; D032446:Myoblasts / Q000502:physiology*; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D054715:Cardiotoxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid