Premium
Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms
Author(s) -
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.
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14367
Subject(s) - actin , skeletal muscle , mitochondrion , myosin , biology , microbiology and biotechnology , endoplasmic reticulum , mitochondrial fission , myofibril , myocyte , endocrinology
While α‐actin isoforms predominate in adult striated muscle, skeletal muscle‐specific knockouts (KOs) of nonmuscle cytoplasmic β cyto ‐ or γ cyto ‐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 β cyto ‐ and γ cyto ‐actin KO mice. We found β cyto ‐ and γ cyto ‐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 β cyto ‐ and/or γ cyto ‐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 β cyto ‐ and γ cyto ‐actin KO mice. Instead, we found that the maximal rate of relaxation after isometric contraction was significantly slowed in muscles of 12‐month‐old β cyto ‐ and γ cyto ‐actin muscle‐specific KO mice. Our data suggest that impaired Ca 2+ re‐uptake may presage development of the observed SR morphological changes in aged mice while providing a potential pathological mechanism for the observed myopathy.