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Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms

O'Rourke, Allison R., Lindsay, Angus, Tarpey, Michael D., Yuen, Samantha, McCourt, Preston, Nelson, D'anna M., Perrin, Benjamin J., Thomas, David D., Spangenburg, Espen E., Lowe, Dawn A., Ervasti, James M.
The FEBS journal 2018 v.285 no.3 pp. 481-500
actin, adults, calcium, fibroblasts, mice, mitochondria, muscles, muscular diseases, myotubes, oxygen consumption, reticulum, sarcoplasmic reticulum, striated muscle, transmission electron microscopy
While 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.