Immune‐Mediated Mechanisms Potentially Regulate the Disease Time‐Course of Duchenne Muscular Dystrophy and Provide Targets for Therapeutic Intervention

Abstract

Duchenne muscular dystrophy is a lethal muscle wasting disease that affects boys. Mutations in the dystrophin gene result in the absence of the dystrophin glycoprotein complex (DGC) from muscle plasma membranes. In healthy muscle fibers, the DGC forms a link between the extracellular matrix and the cytoskeleton to protect against contraction-induced membrane lesions and to regulate cell signaling. The absence of the DGC results in aberrant regulation of inflammatory signaling cascades. Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, but the role and regulation of this process in the disease time course has not been sufficiently examined. The transcription factor, NF-κB has been shown to contribute to the disease process and is likely involved with increased inflammatory gene expression, including cytokines and chemokines, seen in dystrophic muscle. These aberrant signaling processes may regulate the early time course of inflammatory events that contribute to disease onset. This review critically evaluates the possibility that dystrophic muscle lesions in both DMD patients and mdx mice are the result of immune-mediated mechanisms that are regulated by inflammatory signaling and also highlights new therapeutic directions.

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…Absence of dystrophin or other components of the DAPC compromises the integrity of the DAPC itself leading to a susceptibility of myofibers to degeneration during contraction and consequent progressive loss of muscle efficiency [1,2]. The muscle damage subsequent to the absence of dystrophin determines massive infiltration of immune cells in muscle tissue, and the chronic activation of signaling pathways implicated in the inflammatory response [3]. Indeed, muscles of DMD patients are characterized by a condition of chronic inflammation and overexpression of inflammatory genes at the onset and during the progression of the pathology [3,4].…”

“…The muscle damage subsequent to the absence of dystrophin determines massive infiltration of immune cells in muscle tissue, and the chronic activation of signaling pathways implicated in the inflammatory response [3]. Indeed, muscles of DMD patients are characterized by a condition of chronic inflammation and overexpression of inflammatory genes at the onset and during the progression of the pathology [3,4]. Moreover, as a consequence of continuous degeneration/regeneration cycles, during the progression of the disease an exhaustion of the regenerative potential occurs in dystrophic muscles.…”

“…In DMD the lack of dystrophin leads to progressive muscle degeneration, which creates a condition of chronic inflammation that in turn hampers compensatory mechanisms and favors the accumulation of fibrous and adipose tissues [3]. Despite the huge effort to find a cure, corticosteroids remain the gold standard therapy for DMD patients, since the numerous approaches investigated so far have shown several limitations, with most of them requiring a concomitant immunosuppressive treatment.…”

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

“…Although inflammation is the pathological hallmark of dystrophic muscular lesion, the mechanisms influencing muscle fiber pathology are still not fully understood. 2 The deficiency of dystrophin causes plasma-membrane instability that leads to a misfolding of the multimeric complex of dystrophin glycoprotein complex (DGC) and addresses its components to intracellular proteolysis. 3 The ubiquitin-proteasome system is a nonlysosomal, multicatalytic and multisubunit complex involved in the ubiquitin-dependent, selective intracellular degradation of proteins.…”

Altered Gene Expression Pathways in Duchenne Muscular Dystrophy

“…Among the results, it is worth mentioning that the response to the lack of dystrophin varies in different muscle groups of human and mdx mice, and it was proposed that changes in gene expression could be related with the progression of the disease (Porter et al 2003b;Lang et al 2004;Porter et al 2004;Dogra et al 2008). Moreover, some groups studied the profile of gene expression in skeletal muscle implicated in specific pathways such as regeneration (Turk et al 2005), inflammation (Evans et al 2009a), immune system (Evans et al 2009b) and specific transcription factors (Dogra et al 2008). Also there are some studies that propose that expression of utrophin in the mdx mouse muscle results in a gene expression profile that is similar to that seen for the wt mouse (Baban and Davies 2008).…”