Activation of JNK1 contributes to dystrophic muscle pathogenesis

Duchenne Muscular Dystrophy (DMD) originates from deleterious mutations in the dystrophin gene, with a complete loss of the protein product [1, 2]. Su bsequently, the disease is manifested in severe striated muscle wasting and death in early adulthood [3]. Dystrophin provides a structural base for th e assembly of an integral membrane protein complex [4]. As such, dystrophin deficiency leads to an altered mechanical integrity of the myofiber and a predisposition to contraction-induced damage [5-7]. However, the developmen t of myofiber degeneration prior to an observed mechanical defect has been documented in various dystrophic models [8, 9]. Although activation of a de trimental signal transduction pathway has been suggested as a probable caus e, a specific cellular cascade has yet to be defined. Here, it is shown tha t murine models of DMD displayed a muscle-specific activation of JNK1. Inde pendent activation of JNK1 resulted in defects in myotube viability and int egrity in vitro, similar to a dystrophic phenotype. In addition, direct mus cle injection of an adenoviral construct containing the JNK1 inhibitory pro tein, JIP1, dramatically attenuated the progression of dystrophic myofiber destruction. Taken together, these results suggest that a JNK1-mediated sig nal cascade is a conserved feature of dystrophic muscle and contributes to the progression of the disease pathogenesis.