O'Rourke, Allison R.Lindsay, AngusTarpey, Michael D.Yuen, SamanthaMcCourt, PrestonNelson, D'anna M.Perrin, Benjamin J.Thomas, David D.Spangenburg, Espen E.Lowe, Dawn A.Ervasti, James M.2018-01-252018-01-252018O'Rourke, A. R., Lindsay, A., Tarpey, M. D., Yuen, S., McCourt, P., Nelson, D. M., Perrin, B. J., Thomas, D. D., Spangenburg, E. E., Lowe, D. A. and Ervasti, J. M. (2018), Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms. FEBS J. Accepted Author Manuscript. http://dx.doi.org/10.1111/febs.14367https://hdl.handle.net/1805/15070While α-actin isoforms predominate in adult striated muscle, skeletal muscle-specific knockouts (KOs) of nonmuscle cytoplasmic βcyto- or γcyto-actin each cause a mild, but progressive myopathy effected by an unknown mechanism. Using transmission electron microscopy, we identified morphological abnormalities in both the mitochondria and the sarcoplasmic reticulum (SR) in aged muscle-specific βcyto- and γcyto-actin KO mice. We found βcyto- and γcyto-actin proteins to be enriched in isolated mitochondrial-associated membrane preparations, which represent the interface between mitochondria and sarco-endoplasmic reticulum important in signaling and mitochondrial dynamics. We also measured significantly elongated and interconnected mitochondrial morphologies associated with a significant decrease in mitochondrial fission events in primary mouse embryonic fibroblasts lacking βcyto- and/or γcyto-actin. Interestingly, mitochondrial respiration in muscle was not measurably affected as oxygen consumption was similar in skeletal muscle fibers from 12 month-old muscle-specific βcyto- and γcyto-actin KO mice. Instead, we found that the maximal rate of relaxation after isometric contraction was significantly slowed in muscles of 12-month-old βcyto- and γcyto-actin muscle-specific KO mice. Our data suggest that impaired Ca2+ re-uptake may presage development of the observed SR morphological changes in aged mice while providing a potential pathological mechanism for the observed myopathy.enPublisher Policyβ-actinγ-actinisoformsArticle