Dysregulated Intracellular Signaling and Inflammatory Gene Expression During Initial Disease Onset in Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy is a debilitating genetic disorder characterized by severe muscle wasting and early death in affected boys. The primary cause of this disease is mutations in the dystrophin gene that result in the absence of the protein dystrophin and the associated dystrophin-glycoprotein complex in the plasma membrane of muscle fibers. In normal muscle, this complex forms a link between the extracellular matrix and the cytoskeleton that is thought to protect muscle fibers from contraction-induced membrane lesions and to regulate cell signaling cascades. Although the primary defect is known, the mechanisms that initiate disease onset have not been characterized. Data collected during early maturation suggest that inflammatory and immune responses are key contributors to disease pathogenesis and may be initiated by aberrant signaling in dystrophic muscle. However, detailed time course studies of the inflammatory and immune processes are incomplete and need to be characterized further to understand the disease progression. The purposes of this review are to examine the possibility that initial disease onset in dystrophin-deficient muscle results from aberrant inflammatory signaling pathways and to highlight the potential clinical relevance of targeting these pathways to treat Duchenne muscular dystrophy.

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

“…The relationship between reactive inflammation of dystrophic muscles and the role of local concentration of inflammatory cytokines in promoting compensatory regeneration or fibroadipogenic degeneration is still controversial (22). Although the role of chronic inflammation in the pathogenesis of DMD has been firmly established (23) and is well supported by the beneficial effects observed with steroid treatment in DMD patients (4) and antiinflammatory interventions in mdx mice (24), the inflammatory infiltrate also provides a source of environmental cues that can positively affect the activity of the cellular network that promotes muscle regeneration (22). However, over time these beneficial effects can turn into negative ones, with an exhaustion of the regeneration potential of dystrophic muscles and the compensatory repair by fibrosis and fat deposition.…”

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

“…The mdx mouse strain, lacking a functional dystrophin gene, has served as the animal model for human DMD and Becker muscular dystrophies [10]. However, while the skeletal muscles of mdx mice undergo extensive necrosis early in neonatal life, unlike the human disease, the affected muscle rapidly regenerates and regains structural and functional integrity [8,[11][12][13]. The enhanced regenerative potential of mdx muscles and the upregulation of compensatory proteins, such as utrophin and integrins, are thought to be the basis of the reduced wasting of dystrophin-deficient muscles in mdx [14].…”

G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy

“…Patients with DMD show progressive physical impairment leading to the death by 20-30 years of age, whereas a mouse model of DMD (mdx mice) harbouring a dystrophin mutation has minimal physical impairment and a normal lifespan 26 . Indeed, mdx mice appear grossly normal ( Supplementary Fig.…”