Bonifacio 2016 Arch Toxicol

From Bioblast
Publications in the MiPMap
Bonifacio A, Mullen PJ, Mityko IS, Navegantes LC, Bouitbir J, KrΓ€henbΓΌhl S (2016) Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo. Arch Toxicol 90:203-15. doi: 10.1007/s00204-014-1378-4

Β» PMID: 25300705

Bonifacio A, Mullen PJ, Mityko IS, Navegantes LC, Bouitbir J, KrΓ€henbΓΌhl S (2016) Arch Toxicol

Abstract: Simvastatin is effective and well tolerated, with adverse reactions mainly affecting skeletal muscle. Important mechanisms for skeletal muscle toxicity include mitochondrial impairment and increased expression of atrogin-1. The aim was to study the mechanisms of toxicity of simvastatin on H9c2 cells (a rodent cardiomyocyte cell line) and on the heart of male C57BL/6 mice. After, exposure to 10 ΞΌmol/L simvastatin for 24 h, H9c2 cells showed impaired oxygen consumption, a reduction in the mitochondrial membrane potential and a decreased activity of several enzyme complexes of the mitochondrial electron transfer system (ETS). The cellular ATP level was also decreased, which was associated with phosphorylation of AMPK, dephosphorylation and nuclear translocation of FoxO3a as well as increased mRNA expression of atrogin-1. Markers of apoptosis were increased in simvastatin-treated H9c2 cells. Treatment of mice with 5 mg/kg/day simvastatin for 21 days was associated with a 5 % drop in heart weight as well as impaired activity of several enzyme complexes of the ETS and increased mRNA expression of atrogin-1 and of markers of apoptosis in cardiac tissue. Cardiomyocytes exposed to simvastatin in vitro or in vivo sustain mitochondrial damage, which causes AMPK activation, dephosphorylation and nuclear transformation of FoxO3a as well as increased expression of atrogin-1. Mitochondrial damage and increased atrogin-1 expression are associated with apoptosis and increased protein breakdown, which may cause myocardial atrophy.

β€’ Bioblast editor: Gnaiger E β€’ O2k-Network Lab: CH Basel Kraehenbuehl S

Corrections

Communicated by Gnaiger E (2021-12-08)
  • Section "Activity of enzyme complexes of the mitochondrial electron transport chain" - ".. First, we assessed the activity of complex I using glutamate and malate (final concentrations 10 and 5 mmol/L, respectively) as substrates in the presence of ADP (final concentration 2.5 mmol/L)."
Comment: Respirometry assesses pathway capacities, in which respiratory Complexes may operate at various excess capacities that are not assessed by this established approach of measuring OXPHOS capacities based on substrate titrations that activate specific mitochondrial pathways. Supercomplexes may exert an effect on pathway fluxes, and CoQ and cytochrome c may limit pathway flux under pathological conditions, which is different from assessing the activity of enzyme complexes. - See Gnaiger 2020 BEC MitoPathways (page 18): Metabolic pathways are defined by a network of enzymes and metabolites. .. The lack of distinction between the abbreviation of a respiratory Complex (CI, CII) and a pathway (CI, CII) explains the widespread misconception to interpret a diminished OXPHOS capacity of the CI-pathway as a defect of Complex I.
  • "Respiration rates are expressed in picomoles O2 per second per gram wet weight."
Comment: As shown in Figure 5b, respiratory flux of permeabilized muscle fibers were actually expressed in units of picomoles O2 per second per milligram wet weight [pmolΒ·s-1Β·mg-1].


Labels: MiParea: Respiration, Pharmacology;toxicology 


Organism: Rat  Tissue;cell: Heart  Preparation: Permeabilized cells, Permeabilized tissue, Intact cells 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, DQ, CIV, NS  HRR: Oxygraph-2k 


Cookies help us deliver our services. By using our services, you agree to our use of cookies.