title: A Peculiar Formula of Essential Amino Acids Prevents Rosuvastatin Myopathy in Mice.
abstract: Myopathy, characterized by mitochondrial oxidative stress, occurs in ∼10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy.
  
  
  
  Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs-increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy. Antioxid. Redox Signal. 25, 595-608.
authors.affiliation: 1 Department of Public Health, Experimental and Forensic Medicine, Pavia University , Pavia, Italy .
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Antona
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, Milan University , Milan, Italy .
authors.forename: Laura
authors.initials: L
authors.lastname: Tedesco
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, Milan University , Milan, Italy .
authors.forename: Chiara
authors.initials: C
authors.lastname: Ruocco
authors.affiliation: 3 Department of Clinical and Experimental Sciences, Brescia University , Brescia, Italy .
authors.forename: Giovanni
authors.initials: G
authors.lastname: Corsetti
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, Milan University , Milan, Italy .
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ragni
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, Milan University , Milan, Italy .
authors.forename: Andrea
authors.initials: A
authors.lastname: Fossati
authors.affiliation: 4 Department of Molecular and Translational Medicine, Brescia University , Brescia, Italy .
authors.forename: Elisa
authors.initials: E
authors.lastname: Saba
authors.affiliation: 4 Department of Molecular and Translational Medicine, Brescia University , Brescia, Italy .
authors.forename: Francesca
authors.initials: F
authors.lastname: Fenaroli
authors.affiliation: 4 Department of Molecular and Translational Medicine, Brescia University , Brescia, Italy .
authors.forename: Mery
authors.initials: M
authors.lastname: Montinaro
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, Milan University , Milan, Italy .
authors.forename: Michele O
authors.initials: MO
authors.lastname: Carruba
authors.affiliation: 4 Department of Molecular and Translational Medicine, Brescia University , Brescia, Italy .
authors.forename: Alessandra
authors.initials: A
authors.lastname: Valerio
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, Milan University , Milan, Italy .
authors.forename: Enzo
authors.initials: E
authors.lastname: Nisoli
mesh_terms: D000601:Amino Acids, Essential / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000068718:Rosuvastatin Calcium / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000601:Amino Acids, Essential; D017382:Reactive Oxygen Species; D000068718:Rosuvastatin Calcium