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

FEBS J. 2018 Feb;285(3):481-500. doi: 10.1111/febs.14367. Epub 2018 Jan 8.


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.

Keywords: isoforms; mitochondrial dynamics; β-actin; γ-actin.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / genetics
  • Actins / metabolism*
  • Animals
  • Cells, Cultured
  • Cytoplasm / metabolism*
  • Cytoplasm / pathology
  • Cytoplasm / ultrastructure
  • Embryo, Mammalian / cytology
  • In Vitro Techniques
  • Male
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Mitochondria, Liver / ultrastructure
  • Mitochondria, Muscle / metabolism*
  • Mitochondria, Muscle / pathology
  • Mitochondria, Muscle / ultrastructure
  • Mitochondrial Diseases / enzymology
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Mitochondrial Dynamics*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle Fibers, Skeletal / ultrastructure
  • Muscle Relaxation*
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / ultrastructure
  • Muscular Diseases / enzymology
  • Muscular Diseases / metabolism
  • Muscular Diseases / pathology
  • Oxygen Consumption
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Sarcoplasmic Reticulum / metabolism*
  • Sarcoplasmic Reticulum / pathology
  • Sarcoplasmic Reticulum / ultrastructure


  • Actins
  • Protein Isoforms