Activation of JNK1 contributes to dystrophic muscle pathogenesis

Abstract

Duchenne Muscular Dystrophy (DMD) originates from deleterious mutations in the dystrophin gene, with a complete loss of the protein product. Subsequently, the disease is manifested in severe striated muscle wasting and death in early adulthood. Dystrophin provides a structural base for the assembly of an integral membrane protein complex. As such, dystrophin deficiency leads to an altered mechanical integrity of the myofiber and a predisposition to contraction-induced damage. However, the development of myofiber degeneration prior to an observed mechanical defect has been documented in various dystrophic models. Although activation of a detrimental signal transduction pathway has been suggested as a probable cause, a specific cellular cascade has yet to be defined. Here, it is shown that murine models of DMD displayed a muscle-specific activation of JNK1. Independent activation of JNK1 resulted in defects in myotube viability and integrity in vitro, similar to a dystrophic phenotype. In addition, direct muscle injection of an adenoviral construct containing the JNK1 inhibitory protein, JIP1, dramatically attenuated the progression of dystrophic myofiber destruction. Taken together, these results suggest that a JNK1-mediated signal cascade is a conserved feature of dystrophic muscle and contributes to the progression of the disease pathogenesis.

PTEN Contributes to Profound PI3K/Akt Signaling Pathway Deregulation in Dystrophin-Deficient Dog Muscle

“…[17][18][19][21][22][23] Nevertheless, these studies have generally focused on one protein rather than assessing the global changes that may precipitate or exacerbate the pathology. Moreover, they have been mainly performed in the mdx mouse, a model that most likely will exhibit species specific changes that may not be reflected in the course of the human disease.…”

Interacting JNK-docking Sites in MKK7 Promote Binding and Activation of JNK Mitogen-activated Protein Kinases

“…Dependent upon such factors as cell type and the nature of the stimulus, JNK has been shown to promote either cell survival or apoptosis (12)(13)(14). Deregulation of the JNK pathway has been implicated in the pathogenesis of many human diseases such as cancer (15), obesity and diabetes (16), muscular dystrophy (17), arthritis (18), Alzheimer disease (19), and Parkinson disease (20). Inhibition of JNK activity is being considered as a possible therapy for many of these diseases (21)(22)(23)(24).…”

PKC Proteins and Muscular Dystrophy

“…Several reports demonstrated activation of all these kinases in skeletal and cardiac muscle of Duchenne muscular dystrophies [22,23]. Interestingly, MAPKs are targets of PKC proteins.…”