Total Absence of Dystrophin Expression Exacerbates Ectopic Myofiber Calcification and Fibrosis and Alters Macrophage Infiltration Patterns

Young, Chris; Gosselin, Maxime R F; Rumney, Robin M. H.; Oksiejuk, Aleksandra; Chira, Natalia; Bożycki, Łukasz; Matryba, Paweł; Łukasiewicz, Kacper; Kao, Alex; Dunlop, Joseph; Robson, Samuel; Zabłocki, Krzysztof; Górecki, Dariusz C.

doi:10.1016/j.ajpath.2019.09.021

Cited by 20 publications

(22 citation statements)

References 75 publications

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“…DMD pathology being intrinsic to myoblasts has been proposed previously [20] and there has been growing evidence that DMD mutations cause a range of cell-autonomous abnormalities in human and mouse myogenic cells and myoblasts that affect cell division, differentiation, energy metabolism and signalling [22–24,24,27,27,66,68–71]. Interestingly, Dmd mdx cell migration found reduced under physiological stimuli (this work) can be increased in the inflammatory environment [27]. Furthermore, altered proliferation and migration resulting in highly metastatic phenotypes, has been associated with the loss of Dp427 in tumours featuring myogenic differentiation [72].…”

Section: Discussionmentioning

confidence: 99%

Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

Gosselin

Mournetas

Borczyk

et al. 2021

Preprint

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Background. Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease that leads to severe disability and death in young men. DMD is caused by out-of-frame mutations in the largest known gene, which encodes dystrophin. The loss of DMD gene expression manifests in progressive degeneration and wasting of striated muscles aggravated by sterile inflammation. Current conventional treatments are palliative only, whereas experimental therapeutic approaches focus on the re-expression of dystrophin in myofibers. However, recent studies established that DMD pathology begins already in prenatal development prior to myofiber formation while, in adult muscle, it affects satellite (stem) cells and the proper development of myofibers. Regeneration defects that exacerbate muscle degeneration appear to be a good therapeutic target, as maintaining regeneration would counteract muscle wasting. It is also the only feasible treatment in advanced stages of the disease. Yet, it is unknown whether dystrophic myoblasts, the intermediary between satellite cells and myofibers and effectors of muscle growth and repair, are also affected. Therefore, we investigated whether DMD myoblasts show a dystrophic phenotype. Methods and Findings. Using a combination of transcriptomic, molecular, biochemical, and functional analyses we demonstrate, to our knowledge for the first time, convergent cell-autonomous abnormalities in primary mouse and human dystrophic myoblasts. In Dmdmdx mouse myoblasts lacking full-length dystrophin transcripts, expression of 170 other genes was significantly altered. Myod1 (p=2.9e-21) and key muscle genes controlled by MyoD (Myog, Mymk, Mymx, epigenetic regulators, ECM interactors, calcium signaling and fibrosis genes) were significantly downregulated. Gene ontology enrichment analysis indicated significant alterations in genes involved in muscle development and function. These transcriptomic abnormalities translated into increased proliferation (p=3.0e-3), reduced migration towards both sera-rich (p=3.8e-2) and cytokine-containing medium (p=1.0e-2), and significantly accelerated differentiation in 3D organotypic cultures. These altered myoblast functions are essential for muscle regeneration. The defects were caused by the loss of expression of full-length dystrophin as strikingly similar and not exacerbated alterations were also observed in dystrophin-null Dmdmdx-βgeo myoblasts. Furthermore, corresponding abnormalities were identified in human DMD primary myoblasts and in an established dystrophic mouse muscle (SC5) cell line, confirming universal, cross-species and cell-autonomous nature of this defect. Conclusions. These results, for the first time, demonstrate the disease continuum: DMD defects in satellite cells cause myoblast dysfunctions diminishing muscle regeneration, which is essential to counteract myofiber degeneration. Full-length dystrophins play a critical role in these processes. Contrary to the established belief, our data identify myoblasts as a novel and important therapeutic target for treatment of this lethal disease.

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Section: Discussionmentioning

confidence: 99%

Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

Gosselin

Mournetas

Borczyk

et al. 2021

Preprint

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“…Particularly, they develop calcification within skeletal muscle 61 , while in Sgca null mice calcification represents less than 1% of gastrocnemius, quadriceps, triceps, or DIA area 29 . The formation of heterotopic ossification seems to be linked to the total absence of dystrophin expression 62 , indeed in Sgca null mice, α-sarcoglycan is absent but, even if reduced, dystrophin is still present in dystrophic muscles 30 . This could explain differences observed upon ROCK inhibition treatment between these two murine models.…”

Section: Discussionmentioning

confidence: 99%

Selective ablation of Nfix in Macrophages preserves Muscular Dystrophy by inhibiting FAPs-dependent fibrosis

Saclier¹,

G²,

Bonfanti³

et al. 2021

Preprint

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Muscular dystrophies are genetic diseases characterized by chronic inflammation and fibrosis. Macrophages are immune cells that sustain muscle regeneration upon acute injury but seem deleterious in the context of chronic muscle injury such as muscular dystrophies. Here we observed that the number of macrophages expressing the transcription factor Nfix increases in two distinct murine models of muscular dystrophies. Plus, we showed that the deletion of Nfix in macrophages in dystrophic mice delays fibrosis establishment and muscle wasting until 6 months of life. Indeed, macrophages lacking Nfix express more TNFα and less TGFβ1 thus promoting apoptosis of fibro-adipogenic progenitors. Moreover, pharmacological treatment of dystrophic mice with ROCK inhibitor accelerates fibrosis through the increase of Nfix expression by macrophages. Thus, we identify Nfix as a macrophage profibrotic actor in muscular dystrophies, whose inhibition could be a therapeutic way to rescue the dystrophic disease.

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“…mdx betageo : Recently, Young et al., generated a model of mdx with complete loss of dystrophin by introducing a disruption in the reading frame downstream of exon 63: mdx betageo [ 124 ]. These dystrophic mice do not express the full length Dp427 isoform of dystrophin but do express the truncated Dp71 isoform.…”

Section: Histopathology and Animal Models Of Muscular Dystrophiesmentioning

confidence: 99%

“…Calcification was also observed in other limb muscles and in the heart of mdx betageo mice. Interestingly, high numbers of macrophages were found around calcified myofibers [ 124 ]. This model is often compared to the DMD-null mouse model that lack the full length of the dystrophin protein (both Dp71 and DP427 isoforms) [ 125, 126 ].…”

Section: Histopathology and Animal Models Of Muscular Dystrophiesmentioning

confidence: 99%

Macrophages in Skeletal Muscle Dystrophies, An Entangled Partner

Théret

Saclier

Messina

et al. 2022

JND

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While skeletal muscle remodeling happens throughout life, diseases that result in its dysfunction are accountable for many deaths. Indeed, skeletal muscle is exceptionally capable to respond to stimuli modifying its homeostasis, such as in atrophy, hypertrophy, regeneration and repair. In particular conditions such as genetic diseases (muscular dystrophies), skeletal muscle’s capacity to remodel is strongly affected and undergoes continuous cycles of chronic damage. This induces scarring, fatty infiltration, as well as loss of contractibility and of the ability to generate force. In this context, inflammation, primarily mediated by macrophages, plays a central pathogenic role. Macrophages contribute as the primary regulators of inflammation during skeletal muscle regeneration, affecting tissue-resident cells such as myogenic cells and endothelial cells, but also fibro-adipogenic progenitors, which are the main source of the fibro fatty scar. During skeletal muscle regeneration their function is tightly orchestrated, while in dystrophies their fate is strongly disturbed, resulting in chronic inflammation. In this review, we will discuss the latest findings on the role of macrophages in skeletal muscle diseases, and how they are regulated.

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Total Absence of Dystrophin Expression Exacerbates Ectopic Myofiber Calcification and Fibrosis and Alters Macrophage Infiltration Patterns

Cited by 20 publications

References 75 publications

Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

Selective ablation of Nfix in Macrophages preserves Muscular Dystrophy by inhibiting FAPs-dependent fibrosis

Macrophages in Skeletal Muscle Dystrophies, An Entangled Partner

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