Mitophagy protects against statin-mediated skeletal muscle toxicity

Autor(es):Mostrar menos -

Ramesh, Mridula ^[1] ; Campos, Juliane C. ^{[2, 3]} ; Lee, Pamela ^[1] ; Song, Yang ^[3] ; Hernandez, Genaro ^[1] ; Sin, Jon ^[3] ; Tucker, Kyle C. ^[3] ; Saadaeijahromi, Hannaneh ^[3] ; Gurney, Michael ^[1] ; Ferreira, Julio C. B. ^[2] ; Andres, Allen M. ^[3]

Afiliação do(s) autor(es)

^[1] San Diego State Univ, Donald P Shiley BioSci Ctr, San Diego, CA 92182 - USA

^[2] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo - Brazil

^[3] Cedars Sinai Med Ctr, Los Angeles, CA 90048 - USA

• Tipo de documento: Artigo Científico
• Fonte: FASEB JOURNAL; v. 33, n. 11, p. 11857-11869, NOV 2019.
• Citações Web of Science: 0

Resumo

The deleterious effects of statins on skeletal muscle are well known, but the mechanism associated with these effects remains unresolved. Statins are associated with mitochondrial damage, which may contribute to muscle myopathy. Here we demonstrate that simvastatin induces mitophagy in skeletal muscle cells and hypothesized that attenuating this process by silencing the mitophagy adapter p62/sequestosome-1 (SQSTM1) might mitigate myotoxicity. Surprisingly, silencing p62/SQSTM1 in differentiated C2C12 muscle cells exacerbated rather than attenuated myotoxicity. This inhibition of mitophagy in the face of statin challenge correlated with increased release of cytochrome c to the cytosol, activation of caspase-3, and lactate dehydrogenase (LDH) release. Correspondingly, targeted knockdown of Parkin, a canonical E3 ubiquitin ligase important for mitophagy, mirrored the effects of p62/SQSTM1 silencing. To corroborate these findings in vivo, we treated Parkin knockout mice with simvastatin for 2 wk. In line with our findings in vitro, these mitophagy-compromised mice displayed reduced spontaneous activity, loss of grip strength, and increased circulating levels of muscle damage marker LDH. Our findings demonstrate that mitophagy is an important mechanism to resist statin-induced skeletal muscle damage. (AU)

• Processo FAPESP: 16/01633-5 - Papel protetor da estimulação beta2-adrenérgica na disfunção/atrofia muscular esquelética: contribuição do sistema lisossomal-autofágico
• Beneficiário: Juliane Cruz Campos
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado