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

Allison R. O'Rourke, Angus Lindsay, Michael D. Tarpey, Samantha Yuen, Preston McCourt, D'anna M. Nelson, Benjamin J. Perrin, David D. Thomas, Espen E. Spangenburg, Dawn A. Lowe, James M. Ervasti

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)481-500
Number of pages20
JournalFEBS Journal
Volume285
Issue number3
DOIs
StatePublished - Feb 2018

Fingerprint

Mitochondrial Dynamics
Muscle Relaxation
Ablation
Muscle
Actins
Protein Isoforms
Muscles
Knockout Mice
Sarcoplasmic Reticulum
Muscular Diseases
Mitochondria
Isometric Contraction
Striated Muscle
Skeletal Muscle Fibers
Mitochondrial Membranes
Transmission Electron Microscopy
Oxygen Consumption
Endoplasmic Reticulum
Fibroblasts
Respiration

Keywords

  • isoforms
  • mitochondrial dynamics
  • β-actin
  • γ-actin

PubMed: MeSH publication types

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

Cite this

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.

In: FEBS Journal, Vol. 285, No. 3, 02.2018, p. 481-500.

Research output: Contribution to journalArticle

O'Rourke, AR, Lindsay, A, Tarpey, MD, Yuen, S, McCourt, P, Nelson, DM, Perrin, BJ, Thomas, DD, Spangenburg, EE, Lowe, DA & Ervasti, JM 2018, 'Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms', FEBS Journal, vol. 285, no. 3, pp. 481-500. https://doi.org/10.1111/febs.14367
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. / Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms. In: FEBS Journal. 2018 ; Vol. 285, No. 3. pp. 481-500.
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