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.
