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

2021 ◽  
Author(s):  
Marielle Saclier ◽  
Giulia Temponi ◽  
Chiara Bonfanti ◽  
Graziella Messina
Keyword(s):  
Muscle Injury ◽  
Muscle Wasting ◽  
Genetic Diseases ◽  
Acute Injury ◽  
Muscular Dystrophies ◽  
Murine Models ◽  
Rock Inhibitor ◽  
Selective Ablation ◽  
Dystrophic Mice ◽  
Dystrophic Disease

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.

scholarly journals Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

2020 ◽  
Vol 21 (3) ◽  
pp. 932 ◽  
Author(s):  
Piera Filomena Fiore ◽  
Anna Benedetti ◽  
Martina Sandonà ◽  
Luca Madaro ◽  
Marco De Bardi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Muscle Regeneration ◽  
Muscle Wasting ◽  
Expression Level ◽  
Acute Injury ◽  
Mdx Mice ◽  
Muscle Stem Cells ◽  
Advanced Stages ◽  
And Performance ◽  
Dystrophic Mice

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ−/− mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ−/− muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ−/− muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ−/− muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ−/− muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.

scholarly journals Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

2011 ◽  
Vol 17 (5-6) ◽  
pp. 457-465 ◽  
Author(s):  
Silvia Consalvi ◽  
Valentina Saccone ◽  
Lorenzo Giordani ◽  
Giulia Minetti ◽  
Chiara Mozzetta ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Genetic Diseases ◽  
Muscular Dystrophies ◽  
Epigenetic Drugs

Study of myogenic potential of extra cellular vesicles in murine models for muscular dystrophies

2016 ◽  
Vol 26 ◽  
pp. S128
Author(s):  
D. Ayub-Guerrieri ◽  
A. Ribeiro ◽  
R. Ishiba ◽  
L. Yumi ◽  
P. Semedo-Kuriki ◽  
...  
Keyword(s):  
Muscular Dystrophies ◽  
Murine Models ◽  
Myogenic Potential

scholarly journals Cellular and molecular mechanisms underlying muscular dystrophy

2013 ◽  
Vol 201 (4) ◽  
pp. 499-510 ◽  
Author(s):  
Fedik Rahimov ◽  
Louis M. Kunkel
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Neuromuscular Disorders ◽  
Genetic Diseases ◽  
Model Systems ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Progressive Degeneration ◽  
Molecular Pathomechanisms

The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

Age-related differences in diaphragm muscle injury after lengthening activations

1994 ◽  
Vol 77 (5) ◽  
pp. 2125-2133 ◽  
Author(s):  
J. F. Watchko ◽  
B. D. Johnson ◽  
L. E. Gosselin ◽  
Y. S. Prakash ◽  
G. C. Sieck
Keyword(s):  
Muscle Injury ◽  
Diaphragm Muscle ◽  
Acute Injury ◽  
Stimulation Protocol ◽  
Optimal Length ◽  
Adult Rat ◽  
Age Related ◽  
Stimulus Train ◽  
Two Phases

The susceptibility of postnatal day 15 and adult rat diaphragms (DIAs) to acute injury after repetitive isovelocity lengthening activations was examined in vitro. Forces were measured during two phases of each stimulation protocol: 1) isometric phase: during the first 300 ms of each 500-ms train, DIA length was not changed; and 2) isovelocity lengthening phase: during the remaining 200 ms of each stimulus train, DIA was lengthened at a constant velocity from 90 to 110% of optimal length. At maximal activation (75 Hz and a lengthening velocity of 1.0 optimal length per second), the maximum force measured during the isometric phase and that measured during the isovelocity lengthening phase were both greater in adult DIAs than in day 15 DIAs but both declined to a greater extent in adults with repetitive activation. Ultrastructural analysis showed that after lengthening activations muscle fiber injury was very evident in adult but much less prevalent in day 15 DIAs. This difference in susceptibility between the adult and day 15 DIAs did not depend on differences in peak force or absolute velocity of lengthening. We conclude that lengthening activations result in DIA injury and that the adult is more susceptible than its younger counterpart.

scholarly journals Macrophages in Skeletal Muscle Dystrophies, An Entangled Partner

2021 ◽  
pp. 1-23
Author(s):  
Theret Marine ◽  
Saclier Marielle ◽  
Messina Graziella ◽  
Rossi M.V. Fabio
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cells ◽  
Muscle Regeneration ◽  
Genetic Diseases ◽  
Fatty Infiltration ◽  
Skeletal Muscle Regeneration ◽  
Muscular Dystrophies ◽  
Pathogenic Role ◽  
Muscle Remodeling

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.

scholarly journals Muscle satellite cells and impaired late stage regeneration in different murine models for muscular dystrophies

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Antonio F. Ribeiro ◽  
Lucas S. Souza ◽  
Camila F. Almeida ◽  
Renata Ishiba ◽  
Stephanie A. Fernandes ◽  
...  
Keyword(s):  
Satellite Cells ◽  
Late Stage ◽  
Muscular Dystrophies ◽  
Murine Models ◽  
Muscle Satellite Cells

scholarly journals Exploring the Interface between Inflammatory and Therapeutic Glucocorticoid Induced Bone and Muscle Loss

2019 ◽  
Vol 20 (22) ◽  
pp. 5768 ◽  
Author(s):  
Justine M. Webster ◽  
Chloe G. Fenton ◽  
Ramon Langen ◽  
Rowan S. Hardy
Keyword(s):  
Inflammatory Disease ◽  
Muscle Wasting ◽  
Muscle Metabolism ◽  
Chronic Inflammatory Disease ◽  
Muscle Loss ◽  
Murine Models ◽  
Models Of Disease ◽  
Inflammatory Signalling ◽  
Synthetic Glucocorticoids

Due to their potent immunomodulatory anti-inflammatory properties, synthetic glucocorticoids (GCs) are widely utilized in the treatment of chronic inflammatory disease. In this review, we examine our current understanding of how chronic inflammation and commonly used therapeutic GCs interact to regulate bone and muscle metabolism. Whilst both inflammation and therapeutic GCs directly promote systemic osteoporosis and muscle wasting, the mechanisms whereby they achieve this are distinct. Importantly, their interactions in vivo are greatly complicated secondary to the directly opposing actions of GCs on a wide array of pro-inflammatory signalling pathways that underpin catabolic and anti-anabolic metabolism. Several clinical studies have attempted to address the net effects of therapeutic glucocorticoids on inflammatory bone loss and muscle wasting using a range of approaches. These have yielded a wide array of results further complicated by the nature of inflammatory disease, underlying the disease management and regimen of GC therapy. Here, we report the latest findings related to these pathway interactions and explore the latest insights from murine models of disease aimed at modelling these processes and delineating the contribution of pre-receptor steroid metabolism. Understanding these processes remains paramount in the effective management of patients with chronic inflammatory disease.

scholarly journals eATP/P2X7R Axis: An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases

2020 ◽  
Vol 21 (17) ◽  
pp. 5963
Author(s):  
Chiara Panicucci ◽  
Lizzia Raffaghello ◽  
Santina Bruzzone ◽  
Serena Baratto ◽  
Elisa Principi ◽  
...  
Keyword(s):  
Purinergic Signaling ◽  
Genetic Diseases ◽  
Membrane Damage ◽  
Atp Release ◽  
Muscle Membrane ◽  
Muscular Dystrophies ◽  
Inflammasome Activation ◽  
Local Inflammatory Response ◽  
Muscle Plasticity ◽  
Molecular Pattern

In muscle ATP is primarily known for its function as an energy source and as a mediator of the “excitation-transcription” process, which guarantees muscle plasticity in response to environmental stimuli. When quickly released in massive concentrations in the extracellular space as in presence of muscle membrane damage, ATP acts as a damage-associated molecular pattern molecule (DAMP). In experimental murine models of muscular dystrophies characterized by membrane instability, blockade of eATP/P2X7 receptor (R) purinergic signaling delayed the progression of the dystrophic phenotype dampening the local inflammatory response and inducing Foxp3+ T Regulatory lymphocytes. These discoveries highlighted the relevance of ATP as a harbinger of immune-tissue damage in muscular genetic diseases. Given the interactions between the immune system and muscle regeneration, the comprehension of ATP/purinerigic pathway articulated organization in muscle cells has become of extreme interest. This review explores ATP release, metabolism, feedback control and cross-talk with members of muscle inflammasome in the context of muscular dystrophies.

scholarly journals SCA-1 micro-heterogeneity in the fate decision of dystrophic fibro/adipogenic progenitors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Giulio Giuliani ◽  
Simone Vumbaca ◽  
Claudia Fuoco ◽  
Cesare Gargioli ◽  
Ezio Giorda ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Genetic Diseases ◽  
Proliferating Cells ◽  
Pathological Conditions ◽  
Fate Decision ◽  
Cell To Cell Variability ◽  
The Impact ◽  
Dystrophic Mice ◽  
Different Levels

AbstractThe term micro-heterogeneity refers to non-genetic cell to cell variability observed in a bell-shaped distribution of the expression of a trait within a population. The contribution of micro-heterogeneity to physiology and pathology remains largely uncharacterised. To address such an issue, we investigated the impact of heterogeneity in skeletal muscle fibro/adipogenic progenitors (FAPs) isolated from an animal model of Duchenne muscular dystrophy (DMD), the mdx mouse. FAPs play an essential role in muscle homoeostasis. However, in pathological conditions or ageing, they are the source of intramuscular infiltrations of fibrotic or adipose tissue. By applying a multiplex flow cytometry assay, we characterised and purified from mdx muscles two FAP cell states expressing different levels of SCA-1. The two cell states are morphologically identical and repopulate each other after several growth cycles. However, they differ in their in vitro behaviour. Cells expressing higher levels of SCA-1 (SCA1-High-FAPs) differentiate more readily into adipocytes while, when exposed to a fibrogenic stimulation, increase the expression of Col1a1 and Timp1 mRNA. A transcriptomic analysis confirmed the adipogenic propensity of SCA1-High-FAPs. In addition, SCA1-High-FAPs proliferate more extensively ex vivo and display more proliferating cells in dystrophic muscles in comparison to SCA1-Low-FAPs. Adipogenesis of both FAP cell states is inhibited in vitro by leucocytes from young dystrophic mice, while leucocytes isolated from aged dystrophic mice are less effective in limiting the adipogenesis of SCA1-High-FAPs suggesting a differential regulatory effect of the microenvironment on micro-heterogeneity. Our data suggest that FAP micro-heterogeneity is modulated in pathological conditions and that this heterogeneity in turn may impact on the behaviour of interstitial mesenchymal cells in genetic diseases.

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