The non-muscle ADF/cofilin-1 controls sarcomeric actin filament integrity and force production in striated muscle laminopathies

Cell Rep. 2021 Aug 24;36(8):109601. doi: 10.1016/j.celrep.2021.109601.


Cofilins are important for the regulation of the actin cytoskeleton, sarcomere organization, and force production. The role of cofilin-1, the non-muscle-specific isoform, in muscle function remains unclear. Mutations in LMNA encoding A-type lamins, intermediate filament proteins of the nuclear envelope, cause autosomal Emery-Dreifuss muscular dystrophy (EDMD). Here, we report increased cofilin-1 expression in LMNA mutant muscle cells caused by the inability of proteasome degradation, suggesting a protective role by ERK1/2. It is known that phosphorylated ERK1/2 directly binds to and catalyzes phosphorylation of the actin-depolymerizing factor cofilin-1 on Thr25. In vivo ectopic expression of cofilin-1, as well as its phosphorylated form on Thr25, impairs sarcomere structure and force generation. These findings present a mechanism that provides insight into the molecular pathogenesis of muscular dystrophies caused by LMNA mutations.

Keywords: ERK1/2 signaling; cofilin-1; muscular dystrophy; sarcomeric organization; skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Adolescent
  • Adult
  • Animals
  • Cell Line
  • Child
  • Cofilin 1 / metabolism*
  • Destrin / metabolism*
  • Humans
  • Lamin Type A / genetics
  • Lamin Type A / metabolism*
  • Laminopathies / genetics
  • Laminopathies / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Muscle, Striated / metabolism*
  • Muscle, Striated / pathology
  • Muscular Dystrophy, Emery-Dreifuss / genetics
  • Muscular Dystrophy, Emery-Dreifuss / metabolism
  • Mutation
  • Phosphorylation
  • Sarcomeres / metabolism*
  • Signal Transduction
  • Young Adult


  • Cofilin 1
  • DSTN protein, human
  • Destrin
  • LMNA protein, human
  • Lamin Type A
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3