Premium
Mitophagy protects against statin‐mediated skeletal muscle toxicity
Author(s) -
Ramesh idula,
Campos Juliane C.,
Lee Pamela,
Song Yang,
Hernandez Genaro,
Sin Jon,
Tucker Kyle C.,
Saadaeijahromi Hannaneh,
Gurney Michael,
Ferreira Julio C. B.,
Andres Allen M.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900807rr
Subject(s) - mitophagy , skeletal muscle , parkin , c2c12 , simvastatin , myopathy , chemistry , statin , microbiology and biotechnology , pharmacology , biology , endocrinology , autophagy , medicine , biochemistry , myogenesis , apoptosis , disease , parkinson's disease
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.—Ramesh, M., Campos, J. C., Lee, P., Song, Y., Hernandez, G., Sin, J., Tucker, K. C., Saadaeijahromi, H., Gurney, M., Ferreira, J. C. B., Andres, A. M. Mitophagy protects against statin‐mediated skeletal muscle toxicity. FASEB J. 33, 11857‐11869 (2019). www.fasebj.org