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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4037-4047
Number of pages11
JournalFASEB Journal
Volume25
Issue number11
DOIs
Publication statusPublished - Nov 2011

Fingerprint

Myosin Heavy Chains
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Simvastatin
Plasticity
Muscle
Oxidoreductases
Skeletal Muscle
Rats
Muscles
Protein Isoforms
Functional analysis
Rhabdomyolysis
Coenzymes
Biosynthetic Pathways
Muscular Diseases
Hypercholesterolemia
Intraperitoneal Injections
Durability
Cholesterol
Therapeutics

Keywords

  • Cholesterol
  • Statins

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Trapani, L., Melli, L., Segatto, M., Trezza, V., Campolongo, P., Jozwiak, A., ... Pallottini, V. (2011). Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions. FASEB Journal, 25(11), 4037-4047. https://doi.org/10.1096/fj.11-184218

Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions. / Trapani, Laura; Melli, Luca; Segatto, Marco; Trezza, Viviana; Campolongo, Patrizia; Jozwiak, Adam; Swiezewska, Ewa; Pucillo, Leopoldo Paolo; Moreno, Sandra; Fanelli, Francesca; Linari, Marco; Pallottini, Valentina.

In: FASEB Journal, Vol. 25, No. 11, 11.2011, p. 4037-4047.

Research output: Contribution to journalArticle

Trapani, L, Melli, L, Segatto, M, Trezza, V, Campolongo, P, Jozwiak, A, Swiezewska, E, Pucillo, LP, Moreno, S, Fanelli, F, Linari, M & Pallottini, V 2011, 'Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions', FASEB Journal, vol. 25, no. 11, pp. 4037-4047. https://doi.org/10.1096/fj.11-184218
Trapani, Laura ; Melli, Luca ; Segatto, Marco ; Trezza, Viviana ; Campolongo, Patrizia ; Jozwiak, Adam ; Swiezewska, Ewa ; Pucillo, Leopoldo Paolo ; Moreno, Sandra ; Fanelli, Francesca ; Linari, Marco ; Pallottini, Valentina. / Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions. In: FASEB Journal. 2011 ; Vol. 25, No. 11. pp. 4037-4047.
@article{292c2c256b754709aec3a31b610ca3d4,
title = "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.",
keywords = "Cholesterol, Statins",
author = "Laura Trapani and Luca Melli and Marco Segatto and Viviana Trezza and Patrizia Campolongo and Adam Jozwiak and Ewa Swiezewska and Pucillo, {Leopoldo Paolo} and Sandra Moreno and Francesca Fanelli and Marco Linari and Valentina Pallottini",
year = "2011",
month = "11",
doi = "10.1096/fj.11-184218",
language = "English",
volume = "25",
pages = "4037--4047",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "11",

}

TY - JOUR

T1 - Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions

AU - Trapani, Laura

AU - Melli, Luca

AU - Segatto, Marco

AU - Trezza, Viviana

AU - Campolongo, Patrizia

AU - Jozwiak, Adam

AU - Swiezewska, Ewa

AU - Pucillo, Leopoldo Paolo

AU - Moreno, Sandra

AU - Fanelli, Francesca

AU - Linari, Marco

AU - Pallottini, Valentina

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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.

KW - Cholesterol

KW - Statins

UR - http://www.scopus.com/inward/record.url?scp=80355135140&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80355135140&partnerID=8YFLogxK

U2 - 10.1096/fj.11-184218

DO - 10.1096/fj.11-184218

M3 - Article

C2 - 21798954

AN - SCOPUS:80355135140

VL - 25

SP - 4037

EP - 4047

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 11

ER -