title: Alterations in zebrafish development induced by simvastatin: Comprehensive morphological and physiological study, focusing on muscle.
abstract: The cholesterol synthesis inhibitor simvastatin, which is used to treat cardiovascular diseases, has severe collateral effects. We decided to comprehensively study the effects of simvastatin in zebrafish development and in myogenesis, because zebrafish has been used as a model to human diseases, due to its handling easiness, the optical clarity of its embryos, and the availability of physiological and structural methodologies. Furthermore, muscle is an important target of the drug. We used several simvastatin concentrations at different zebrafish developmental stages and studied survival rate, morphology, and physiology of the embryos. Our results show that high levels of simvastatin induce structural damage whereas low doses induce minor structural changes, impaired movements, and reduced heart beating. Morphological alterations include changes in embryo and somite size and septa shape. Physiological changes include movement reduction and slower heartbeat. These effects could be reversed by the addition of exogenous cholesterol. Moreover, we quantified the total cell number during zebrafish development and demonstrated a large reduction in cell number after statin treatment. Since we could classify the alterations induced by simvastatin in three distinct phenotypes, we speculate that simvastatin acts through more than one mechanism and could affect both cell replication and/or cell death and muscle function. Our data can contribute to the understanding of the molecular and cellular basis of the mechanisms of action of simvastatin.
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil.
authors.forename: Laise M
authors.initials: LM
authors.lastname: Campos
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Rios
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil.
authors.forename: Livia
authors.initials: L
authors.lastname: Guapyassu
authors.affiliation: Laboratório de Ultraestrutura Celular, Universidade Santa Úrsula, RJ 22231-010, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Midlej
authors.affiliation: Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil.
authors.forename: Georgia C
authors.initials: GC
authors.lastname: Atella
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil.
authors.forename: Suzana
authors.initials: S
authors.lastname: Herculano-Houzel
authors.affiliation: Laboratório de Ultraestrutura Celular, Universidade Santa Úrsula, RJ 22231-010, Brazil.
authors.forename: Marlene
authors.initials: M
authors.lastname: Benchimol
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mermelstein
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil manoelluiscosta@ufrj.br.
authors.forename: Manoel L
authors.initials: ML
authors.lastname: Costa
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D064347:Microscopy, Electrochemical, Scanning; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development*; D019821:Simvastatin / Q000494:pharmacology*; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development* / Q000502:physiology
chemical_list: D000924:Anticholesteremic Agents; D019821:Simvastatin
keywords: Animal model of human disease; cell proliferation; cholesterol; muscle differentiation; simvastatin; zebrafish embryo