Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions.

Abstract

The rate-limiting step of cholesterol biosynthetic pathway is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme reductase (HGMR), whose inhibitors, the statins, widely used in clinical practice to treat hypercholesterolemia, often cause myopathy, and rarely rhabdomyolysis. All studies to date are limited to the definition of statin-induced myotoxicity omitting to investigate whether and how HMGR inhibition influences muscle functions. To this end, 3-mo-old male rats (Rattus norvegicus) were treated for 3 wk with a daily intraperitoneal injection of simvastatin (1.5 mg/kg/d), and biochemical, morphological, mechanical, and functional analysis were performed on extensor digitorum longus (EDL) muscle. Our results show that EDL muscles from simvastatin-treated rats exhibited reduced HMGR activity; a 15% shift from the fastest myosin heavy-chain (MHC) isoform IIb to the slower IIa/x; and reduced power output and unloaded shortening velocity, by 41 and 23%, respectively, without any change in isometric force and endurance. Moreover, simvastatin-treated rats showed a decrease of maximum speed reached and the latency to fall off the rotaroad (∼-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.

• Authors: Laura Trapani, Luca Melli, Marco Segatto, Viviana Trezza, Patrizia Campolongo, Adam Jozwiak, Ewa Swiezewska, Leopoldo Paolo Pucillo, Sandra Moreno, Francesca Fanelli, Marco Linari, Valentina Pallottini
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 25 Issue 11 Pg. 4037-47 (Nov 2011) ISSN: 1530-6860 [Electronic] United States
• PMID: 21798954 (Publication Type: Journal Article)

Chemical References

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Protein Isoforms
• Simvastatin
• Myosin Heavy Chains

Topics

• Animals
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Male
• Motor Activity (drug effects)
• Muscle Contraction (drug effects, physiology)
• Muscle, Skeletal (drug effects, physiology)
• Myosin Heavy Chains (metabolism)
• Protein Isoforms (drug effects)
• Rats
• Rats, Wistar
• Simvastatin (pharmacology)