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

Nicolas Vignier,Maria Chatzifrangkeskou,Hugo Wioland,Coline Macquart,Caroline Le Dour,Gisèle Bonne,Antoine Jégou,Cécile Peccate,Déborah Cardoso,Thibaut Marais,Naïra Naouar,Guillaume Romet-Lemonne,Alain Schmitt,Wei Wu,Luca Pinton,Maud Beuvin,Francesco Saverio Tedesco,Antoine Muchir,Howard J Worman,Maria Grazia Biferi ,V Decostre ,Mégane Lemaître

doi:10.1016/j.celrep.2021.109601

Abstract

SummaryCofilins 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.

Highlights

LMNA encodes lamin A and lamin C, two components of the nuclear lamina that are essential for nuclear architecture and regulation of chromatin organization (Aebi et al, 1986; Dechat et al, 2008; Lin and Worman, 1993)
LMNA mutations are responsible for autosomal forms of Emery-Dreifuss muscular dystrophy (EDMD) (Bonne et al, 1999), a disorder characterized by progressive muscle weakness and wasting associated with early contractures and dilated cardiomyopathy (Emery, 1987)
Skeletal muscle pathology in soleus from Lmnap.H222P/H222P mice Severe cytoarchitectural abnormalities of skeletal muscles, in soleus muscle, associated with increased connective tissue have been previously observed in Lmnap.H222P/H222P mice, a mouse model of muscular dystrophy caused by LMNA mutations (Arimura et al, 2005)

Summary

Introduction

LMNA encodes lamin A and lamin C, two components of the nuclear lamina that are essential for nuclear architecture and regulation of chromatin organization (Aebi et al, 1986; Dechat et al, 2008; Lin and Worman, 1993). LMNA mutations cause limb girdle muscular dystrophy (Muchir et al, 2000), congenital muscular dystrophy (Quijano-Roy et al, 2008), or isolated cardiomyopathy without skeletal muscle involvement (Fatkin et al, 1999), expanding the phenotypic spectrum of striated muscle diseases linked to mutant A-type nuclear lamins. Despite the recent advances in deciphering the clinical description of muscular dystrophy caused by LMNA mutations (Madej-Pilarczyk, 2018), the molecular mechanisms leading to skeletal muscle damage remain to be determined. Loss of structural function and altered activation of tissue-specific signaling pathways have been proposed to partially explain the striated muscle dysfunction in these diseases (Brull et al, 2018). We have previously shown that the extracellular signal-regulated kinase 1/2 (ERK1/ 2) activity was altered in the affected skeletal muscles expressing disease-causing A-type lamins variants, participating in

Methods

Results

Discussion

Conclusion