Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy

Pessina, Patrizia; Cabrera, Daniel; Morales, María Gabriela; Riquelme, Cecilia; Gutiérrez, Jaime; Serrano, Antonio L.; Brandan, Enrique; Muñoz‐Cánoves, Pura

doi:10.1186/2044-5040-4-7

Cited by 85 publications

(94 citation statements)

References 42 publications

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“…In osteopontin and dystrophin double knockout mice, this matricellular protein acts as an immune-modulator in skeletal muscle and a pro-fibrotic cytokine in muscular dystrophy (73). Dysregulation of both osteopontin and periostin is an early feature in laminin-deficient muscular dystrophy (74, 75); indicating that changed levels of both these matricellular proteins are key factors involved in development of muscular dystrophy related fibrosis(76). These studies clearly establish matricellular proteins as promising therapeutic targets for reducing fibrosis in muscular dystrophy.…”

Section: Discussionmentioning

confidence: 99%

Benfotiamine reduces pathology and improves muscle function in mdx mice

Woodman

et al. 2018

Preprint

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Duchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease which arises from mutations in the dystrophin gene (DMD) that result in the absence or severe reduction of the cytoskeletal protein dystrophin. In addition to the primary dystrophin defect, secondary processes such as inflammation, calcium influx, dysregulated autophagy and fibrosis exacerbate dystrophic pathology and thus increase disease progression. While therapies to restore dystrophin deficiency are being developed, strategies which target these secondary processes could be of benefit to patients. Benfotiamine is a lipid soluble precursor to thiamine that can reduce secondary processes such as inflammation and oxidative stress in diabetic patients. As such we tested it in the mdx mouse model of DMD and found that benfotiamine reduced multiple markers of dystrophic pathology and improved grip strength. In addition, members of the utrophin and dystrophin glycoprotein complexes were significantly increased at the sarcolemma which could improve cell adhesion. We also demonstrated that benfotiamine treatment lowered the expression of macrophage markers and pro-inflammatory cytokines suggesting that benfotiamine is reducing dystrophic pathology by acting on inflammatory processes.

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Section: Discussionmentioning

confidence: 99%

Benfotiamine reduces pathology and improves muscle function in mdx mice

Woodman

et al. 2018

Preprint

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“…The stiffness of the ECM relative to the fibre significantly affected the degree to which disease progression influenced the fascicle stiffness and membrane strain. Interestingly, other studies focusing on fibrosis in DMD have asserted that fibrosis not only exacerbates disease progression, but may also prevent the success of many targeted gene therapies [20,35,36]. Further, the mechanical properties of fibrosis are likely altered throughout the course of disease, as its stiffness has been correlated with both the amount of collagen and the number of cross-links [5,37,38].…”

Section: Discussionmentioning

confidence: 99%

“…While the current standard treatment is corticosteroids, it is merely palliative to prolong ambulation [14 -16]. Several animal models of the disease have been developed-including zebrafish [17,18], mouse [19,20] and canine [21,22]; however, there are still unanswered questions regarding the role of dystrophin in muscle function and how this leads to progressive muscle wasting in DMD. How does the protein protect the cell membrane from mechanical damage?…”

Section: Introductionmentioning

confidence: 99%

Multiscale models of skeletal muscle reveal the complex effects of muscular dystrophy on tissue mechanics and damage susceptibility

et al. 2015

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Computational models have been increasingly used to study the tissue-level constitutive properties of muscle microstructure; however, these models were not created to study or incorporate the influence of disease-associated modifications in muscle. The purpose of this paper was to develop a novel multiscale muscle modelling framework to elucidate the relationship between microstructural disease adaptations and modifications in both mechanical properties of muscle and strain in the cell membrane. We used an agent-based model to randomly generate new muscle fibre geometries and mapped them into a finite-element model representing a cross section of a muscle fascicle. The framework enabled us to explore variability in the shape and arrangement of fibres, as well as to incorporate disease-related changes. We applied this method to reveal the trade-offs between mechanical properties and damage susceptibility in Duchenne muscular dystrophy (DMD). DMD is a fatal genetic disease caused by a lack of the transmembrane protein dystrophin, leading to muscle wasting and death due to cardiac or pulmonary complications. The most prevalent microstructural variations in DMD include: lack of transmembrane proteins, fibrosis, fatty infiltration and variation in fibre cross-sectional area. A parameter analysis of these variations and case study of DMD revealed that the nature of fibrosis and density of transmembrane proteins strongly affected the stiffness of the muscle and susceptibility to membrane damage.

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“…Most studies that have analyzed the treadmill training on mdx mice model used a high intensity of training. This high intensity treadmill training has shown deleterious effects on dystrophic muscle such as higher amount of muscle injury area (Capogrosso et al 2017), fragmented sarcoplasm, inflammatory cells (Radley-Crabb et al, 2012), higher muscular fibrosis area and increased collagen fibers Type I (Pessina et al, 2014) on exercised mdx mice.…”

Section: Discussionmentioning

confidence: 99%

Low Intensity Training Provokes Adaptations on Muscle Fibrosis of a Muscular Dystrophy Model

et al. 2018

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SUMMARY:Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder with progressive clinical signs until death, around the second decade of life. Mdx is the most used animal model to pre-clinical studies of DMD. Parameters of exercise on this muscular disease are still unknown. This research aimed to investigate if the low intensity treadmill training would exacerbate the markers of muscle injury, fibrosis, and the composition of the extracellular matrix by type I and III collagens of the mdx model. Dystrophic 11-week-old male mice were separated in exercised (mdxE, n=8) and sedentary (mdxC, n=8) groups. Wild-type mice were used as control (WT, n=8). Exercised group underwent a LIT protocol (9 m/min, 30min, 3days/week, 60 days) on a horizontal treadmill. Gastrocnemius muscle was collected at day 60 and processed to morphological and morphometric analyzes. Sedentary mdx animals presented inflammatory infiltrate and necrotic fibers. Histochemical analysis revealed that the perimysium of the mdxC group is organized into thick and clustered collagen fibers, which generates a larger area of intramuscular collagen fibers for these animals. Histomorphometry attested that fraction area of collagen fibers of mdxC group was higher than mdxE group (p=0.04) and mdxE group values similar to WT group (p=1.00). Centrally located nuclei fibers and the variance coefficient (VC) of minimal Feret's diameter was similar in mdxE and mdxC groups (p=1.00) and both groups presented higher mean values than WT group (p<0.00). Immunohistochemistry revealed the presence of type I collagen mainly in the mdxC group. LIT protocol had not exacerbated muscle injuries resulting from the dystrophindeficiency membrane fragility at the same time that had reduced the intramuscular collagen deposition. LIT had positively influenced these markers of dystrophic muscle injury on gastrocnemius muscle of mdx model.

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Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy

Cited by 85 publications

References 42 publications

Benfotiamine reduces pathology and improves muscle function in mdx mice

Benfotiamine reduces pathology and improves muscle function in mdx mice

Multiscale models of skeletal muscle reveal the complex effects of muscular dystrophy on tissue mechanics and damage susceptibility

Low Intensity Training Provokes Adaptations on Muscle Fibrosis of a Muscular Dystrophy Model

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