Emery-Dreifuss muscular dystrophy is characterized by skeletal muscle atrophy and weakness, associated with dilated cardiomyopathy and cardiac conduction disorders. Although the genetic causes of this disease have been identified since the 1990s, the molecular and cellular mechanisms that underlie the loss of muscular strength in patients are still a riddle. We have recently shown that abnormal activation of the ERK1/2 pathway in striated muscle from patients and study models of the pathology, triggered the phosphorylation and activation of cofilin-1 on amino acid Thr25, a protein known to participate in the actin network depolymerization. However, the role of this Thr25 phosphorylated form of cofilin-1 in the structure and function of pathological muscle remained unknown. We have demonstrated that cofilin-1 abnormally phosphorylated at Thr25 is protected from degradation by the proteasome, leading to its abnormal accumulation in striated muscle. This results in actin depolymerization at the sarcomere, the contractile unit of striated muscle, and a loss of force production. These results are important both for a better understanding of the pathophysiology of Emery-Dreifuss muscular dystrophy, but also in terms of therapeutic approaches.