Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy

Abstract

In Duchenne muscular dystrophy, asynchronous regeneration in microenvironments within muscle tissue results in development of fibrosis in lieu of global muscle recovery.

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

“…The gradual loss of muscle tissue that occurs in patients affected by DMD has been attributed to an impaired regeneration process and to the progressive alteration of stem cell function in response to the chronic stimuli resulting from the constant repair of degenerating muscle fibers [33,34]. Indeed, repeated cycles of muscle degeneration and regeneration are key features of DMD pathology.…”

Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

“…Indeed, timing plays a crucial role in muscle remodeling. For instance, Dadgar et al (2014) demonstrated that asynchrony drives fibrosis and regeneration failure in the mdx model, finding a link between profound deregulation of global muscle transcription and the muscle damage seen in various dystrophies, including dystrophinopathies and several LGMD types. In addition, BMAL1 has recently been found to be involved in myogenic response to muscle damage, orchestrating the regeneration processes in adult skeletal muscle (Chatterjee et al, 2015).…”

“…It appears that CLOCK gene deregulation could provide a link between autophagy, mitochondrial abnormalities and ColVI diseases. In light of the asynchrony recently described as the mechanism driving regeneration failure (Dadgar et al, 2014), this relationship could be expressed as one of the two following scenarios. First, that circadian rhythm deregulation is a downstream effect of ColVI deficiency and contributes to muscle damage pathogenesis (Fig.…”

“…Timing and synchronization might have different effects on gene expression, depending on the specific gene mutation (COL6 or DMD). Different key regulators, such as AKT1 for COL6 myopathies and TGFB1 for dystrophin mutations (Dadgar et al, 2014), might be implicated, as these two muscle diseases have different pathogenic signatures, represented by defective autophagy and massive muscle necrosis, respectively. Finally, given that CLOCK is downregulated only in the severe UCMD phenotype, it should be further explored as a severity biomarker in patients with myopathies characterized by a severe muscle remodeling, with a view to applications in both disease stratification in patients and monitoring in clinical trials.…”

Inflammation et régénération musculaire

“…Cependant, une infiltration chronique, ou mal coordonnée, de ces divers types cellulaires peut nuire à la régénération musculaire. Ainsi, des blessures musculaires successives induites par deux injections de notexine 2 séparées de quelques jours, provoquent une régénération musculaire asynchrone, un recrutement leucocytaire chronique et augmentent la fibrose tissulaire [31]. Plusieurs conditions SYNTHÈSE REVUES à long terme, la dysfonction musculaire des souris dystrophiques.…”