Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms. (8th January 2018)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: FEBS journal. Volume 285:Number 3(2018)
• Page Start: 481
• Page End: 500
• Publication Date: 2018-01-08
• Subjects: β‐actin -- γ‐actin -- isoforms -- mitochondrial dynamics; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14367
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : 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 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. Abstract : Gene knockout (KO) of either cytoplasmic actin isoform (βcyto‐ or γcyto‐actin) results in elongated mitochondrial morphology and decreased mitochondrial fission in mouse embryonic fibroblasts. Ablation of either βcyto‐ or γcyto‐actin in skeletal muscle also results in altered mitochondrial and sarcoplasmic reticulum morphologies in aged skeletal muscle, as well as impaired skeletal muscle relaxation.