Pravastatin Chronic Treatment Sensitizes Hypercholesterolemic Mice Muscle to Mitochondrial Permeability Transition: Protection by Creatine or Coenzyme Q(10)

Author(s)

Busanello, Estela N. B. ; Marques, Ana C. ; Lander, Noelia ; de Oliveira, Diogo N. ; Catharino, Rodrigo R. ; Oliveira, Helena C. F. ; Vercesi, Anibal E.

• Document type: Journal article
• Source: FRONTIERS IN PHARMACOLOGY; v. 8, APR 5 2017.
• Web of Science Citations: 15

Abstract

Statins are efficient cholesterol-lowering medicines utilized worldwide. However, 10% of patients suffer from adverse effects specially related to skeletal muscle function. Pro- or anti-oxidant effects of statins have been reported. Here we hypothesized that statins induce muscle mitochondrial oxidative stress leading to mitochondrial permeability transition (MPT) which may explain statin muscle toxicity. Thus, our aims were to investigate the effects of statin chronic treatment on muscle mitochondrial respiration rates, MPT and redox state indicators in the context of hypercholesterolemia. For this purpose, we studied muscle biopsies of the hypercholesterolemic LDL receptor knockout mice (LDLr-/-) treated with pravastatin during 3 months. Plantaris, but not soleus muscle of treated mice showed significant inhibition of respiration rates induced by ADP (-14%), oligomycin (-20%) or FCCP (-40%). Inhibitions of respiratory rates were sensitive to EGTA (Ca2+ chelator), cyclosporin A (MPT inhibitor), ruthenium red (inhibitor of mitochondria Ca2+ uptake) and coenzyme Q(10) (antioxidant), indicating that pravastatin treatment favors Ca2+ induced MPT. Diet supplementation with creatine (antioxidant) also protected treated mice against pravastatin sensitization to Ca2+ induced MPT. Among several antioxidant enzymes analyzed, only catalase activity was increased by 30% in plantaris muscle of pravastatin treated mice. Oxidized lipids, but not proteins biomarkers were identified in treated LDLr-/- plantaris muscle. Taken together, the present results suggest that chronic pravastatin administration to a model of familial hypercholesterolemia promotes mitochondrial dysfunctions in plantaris muscle that can be counteracted by antioxidants administered either in vitro (CoQ(10)) or in vivo (creatine). Therefore, we propose that inhibition of muscle mitochondrial respiration by pravastatin leads to an oxidative stress that, in the presence of calcium, opens the permeability transition pore. This mitochondrial oxidative stress caused by statin treatment also signals for cellular antioxidant system responses such as catalase upregulation. These results suggest that the detrimental effects of statins on muscle mitochondria could be prevented by co-administration of a safe antioxidant such as creatine or CoQ10. (AU)

• FAPESP's process: 14/00084-2 - Identification of adulterations and simultaneous determination of nutrients and contaminants in food using direct analysis mass spectrometry and imaging
• Grantee: Diogo Noin de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/11261-2 - Cellular antioxidant systems response to mitochondrial oxidative stress induced by statins in skelton muscle of hypercholesterolemic mice
• Grantee: Estela Natacha Brandt Busanello
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/08995-4 - Calcium signaling in trypanosomatids
• Grantee: Noelia Marina Lander Manfredi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants