When the ERK1/2 pathway disrupts the sarcomere and impairs muscle strength

Emery-Dreifuss muscular dystrophy is characterised by skeletal muscle loss and weakness, associated with dilated cardiomyopathy and cardiac conduction disorders. Although the genetic cause of this disorder has been known since the 1990s(1,2), the molecular and cellular mechanisms behind loss of strength in these patients remain unclear. 

We recently showed that abnormal activation of the ERK1/2 pathway in striated muscle in patients and analytical models of the disease(3,4) led to phosphorylation and activation of cofilin 1, a protein known to contribute to depolymerisation of the actin network(5). However, the role of this phosphorylated form of cofilin 1 in pathological muscle structure and function remained unknown. We recently demonstrated that abnormally phosphorylated cofilin 1 was protected from degradation by the proteasome, leading to its abnormal accumulation in striated muscle. This leads to depolymerisation of actin in the sarcomere, the contractile unit of striated muscle, and loss of muscle force production(6). 

These results are important for shedding light on the pathophysiology of Emery-Dreifuss muscular dystrophy, and also in terms of therapeutic strategy. 


(1) Bione S, et al. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat. Genet. 1994, 8:323-7.

(2) Bonne G, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat. Genet. 1999, 21:285-8.

(3) Muchir A, et al. Activation of MAPK Pathway Links LMNA Mutations to Cardiomyopathy in Emery-Dreifuss Muscular Dystrophy. J. Clin. Invest. 2007, 117:1282-1293.

(4) Muchir A, et al. Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation. Skelet. Muscle. 2013, 3:17.

(5) Chatzifrangkeskou M, et al. Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation. Hum. Mol. Genet. 2018, 27:3060-3078.


(6) Vignier N, et al. The non-muscle ADF/cofilin-1 controls sarcomeric actin filament integrity and force production in striated muscle laminopathies. Cell Reports. 2021, in press.