scholarly journals Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype

2016 ◽  
Vol 213 (2) ◽  
pp. 275-288 ◽  
Author(s):  
Joana Capote ◽  
Irina Kramerova ◽  
Leonel Martinez ◽  
Sylvia Vetrone ◽  
Elisabeth R. Barton ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Macrophage Polarization ◽  
Inflammatory Cells ◽  
Mdx Mice ◽  
Muscle Weight ◽  
Cell Counts ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
And Function

In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors.

Exercise and clenbuterol as strategies to decrease the progression of muscular dystrophy in mdx mice

1996 ◽  
Vol 80 (3) ◽  
pp. 734-741 ◽  
Author(s):  
E. E. Dupont-Versteegden
Keyword(s):  
Body Weight ◽  
Muscular Dystrophy ◽  
Weight Ratio ◽  
Morphological Characteristics ◽  
Mdx Mice ◽  
Body Weight Ratio ◽  
Muscle Weight ◽  
Sedentary Group ◽  
Running Activity ◽  
Tetanic Tension

The effects of exercise and the combination of exercise and clenbuterol on progression of muscular dystrophy were studied in mdx mice. At 3 wk of age, mdx mice were randomly assigned to sedentary (MS), exercise (ME), or combined exercise and clenbuterol (MEC) groups. Clenbuterol was given in the drinking water (1.0-1.5 mg . kg body weight-1 . day-1), and exercise consisted of spontaneous running activity on exercise wheels. At 3 mo or 1 yr of age, ventilatory function, contractile properties, and morphological characteristics of the soleus (Sol) and diaphragm (Dia) muscles were measured. The mdx mice receiving clenbuterol ran less than the mice without clenbuterol. The combination of clenbuterol and exercise was associated with an increase in Sol muscle weight and a muscle weight-to-body weight ratio of 30-35% compared with the sedentary group and approximately 20% compared to exercise alone. Myosin and total protein concentrations of the Sol and Dia increased in the MEC group at 1 yr of age only. Normalized active tension was increased in the Dia at 1 yr of age in both the ME and MEC groups by approximately 30%. Absolute tetanic tension of the Sol was increased at both 3 mo and 1 yr of age in the MEC compared with the MS group. At 1 yr of age, there was an additional 23% increase compared with the ME group. Fatigability increased in the MEC group by approximately 25% in the Sol and Dia muscles at both ages compared with the MS and ME groups. Results indicate that exercise and exercise plus clenbuterol decrease the progression of muscular dystrophy. However, different mechanisms may be involved because the combination of clenbuterol and exercise resulted in increased fatigability and the development of deformities, whereas exercise alone did not. Therefore, clenbuterol may not be suitable for use in patients with muscular dystrophy.

scholarly journals PAI-1–regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy

2012 ◽  
Vol 196 (1) ◽  
pp. 163-175 ◽  
Author(s):  
Esther Ardite ◽  
Eusebio Perdiguero ◽  
Berta Vidal ◽  
Susana Gutarra ◽  
Antonio L. Serrano ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Transforming Growth Factor ◽  
Proteolytic Processing ◽  
Mdx Mice ◽  
Muscle Fibrosis ◽  
Type Plasminogen Activator ◽  
Important Regulator ◽  
Muscle Homeostasis ◽  
Phosphatase And Tensin Homologue ◽  
Pai 1

Disruption of skeletal muscle homeostasis by substitution with fibrotic tissue constitutes the principal cause of death in Duchenne muscular dystrophy (DMD) patients, yet the implicated fibrogenic mechanisms remain poorly understood. This study identifies the extracellular PAI-1/urokinase-type plasminogen activator (uPA) balance as an important regulator of microribonucleic acid (miR)–21 biogenesis, controlling age-associated muscle fibrosis and dystrophy progression. Genetic loss of PAI-1 in mdx dystrophic mice anticipated muscle fibrosis through these sequential mechanisms: the alteration of collagen metabolism by uPA-mediated proteolytic processing of transforming growth factor (TGF)–β in muscle fibroblasts and the activation of miR-21 expression, which inhibited phosphatase and tensin homologue and enhanced AKT signaling, thus endowing TGF-β with a remarkable cell proliferation–promoting potential. Age-associated fibrogenesis and muscle deterioration in mdx mice, as well as exacerbated dystrophy in young PAI-1−/− mdx mice, could be reversed by miR-21 or uPA-selective interference, whereas forced miR-21 overexpression aggravated disease severity. The PAI-1–miR-21 fibrogenic axis also appeared dysregulated in muscle of DMD patients, providing a basis for effectively targeting fibrosis and muscular dystrophies in currently untreatable individuals.

scholarly journals Regulation of α5β1 integrin conformation and function by urokinase receptor binding

2005 ◽  
Vol 168 (3) ◽  
pp. 501-511 ◽  
Author(s):  
Ying Wei ◽  
Ralf-Peter Czekay ◽  
Liliane Robillard ◽  
Matthias C. Kugler ◽  
Feng Zhang ◽  
...  
Keyword(s):  
Cell Attachment ◽  
Alternative Activation ◽  
Cis Acting ◽  
Type Iii ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Β1 Integrins ◽  
Direct Binding ◽  
And Function ◽  
Interfering Rna

Urokinase-type plasminogen activator receptors (uPARs), up-regulated during tumor progression, associate with β1 integrins, localizing urokinase to sites of cell attachment. Binding of uPAR to the β-propeller of α3β1 empowers vitronectin adhesion by this integrin. How uPAR modifies other β1 integrins remains unknown. Using recombinant proteins, we found uPAR directly binds α5β1 and rather than blocking, renders fibronectin (Fn) binding by α5β1 Arg-Gly-Asp (RGD) resistant. This resulted from RGD-independent binding of α5β1–uPAR to Fn type III repeats 12–15 in addition to type III repeats 9–11 bound by α5β1. Suppression of endogenous uPAR by small interfering RNA in tumor cells promoted weaker, RGD-sensitive Fn adhesion and altered overall α5β1 conformation. A β1 peptide (res 224NLDSPEGGF232) that models near the known α-chain uPAR-binding region, or a β1-chain Ser227Ala point mutation, abrogated effects of uPAR on α5β1. Direct binding and regulation of α5β1 by uPAR implies a modified “bent” integrin conformation can function in an alternative activation state with this and possibly other cis-acting membrane ligands.

scholarly journals Urokinase-type plasminogen activator (uPA) regulates the expression and function of growth-associated protein 43 (GAP-43) in the synapse

2019 ◽  
Vol 295 (2) ◽  
pp. 619-630 ◽  
Author(s):  
Paola Merino ◽  
Ariel Diaz ◽  
Enrique R. Torre ◽  
Manuel Yepes
Keyword(s):  
Plasminogen Activator ◽  
Cortical Neurons ◽  
Release Site ◽  
Axonal Growth ◽  
Presynaptic Terminals ◽  
Type Plasminogen Activator ◽  
Mature Brain ◽  
Urokinase Type Plasminogen Activator ◽  
Vesicle Cycle ◽  
And Function

Growth-associated protein 43 (GAP-43) plays a central role in the formation of presynaptic terminals, synaptic plasticity, and axonal growth and regeneration. During development, GAP-43 is found in axonal extensions of most neurons. In contrast, in the mature brain, its expression is restricted to a few presynaptic terminals and scattered axonal growth cones. Urokinase-type plasminogen activator (uPA) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin and activates signaling pathways that promote cell migration, proliferation, and survival. In the developing brain, uPA induces neuritogenesis and neuronal migration. In contrast, the expression and function of uPA in the mature brain are poorly understood. However, recent evidence reveals that different forms of injury induce release of uPA and expression of uPAR in neurons and that uPA/uPAR binding triggers axonal growth and synapse formation. Here we show that binding of uPA to uPAR induces not only the mobilization of GAP-43 from the axonal shaft to the presynaptic terminal but also its activation in the axonal bouton by PKC-induced calcium-dependent phosphorylation at Ser-41 (pGAP-43). We found that this effect requires open presynaptic N-methyl-d-aspartate receptors but not plasmin generation. Furthermore, our work reveals that, following its activation by uPA/uPAR binding, pGAP-43 colocalizes with presynaptic vesicles and triggers their mobilization to the synaptic release site. Together, these data reveal a novel role of uPA as an activator of the synaptic vesicle cycle in cerebral cortical neurons via its ability to induce presynaptic recruitment and activation of GAP-43.

Evaluation of Fibrinolytic Capacity in Plasma during Thrombolytic Therapy with Single (scu-PA) or Two-chain Urokinase Type Plasminogen Activator (tcu-PA) by a Combined Assay System for Urokinase Type Plasminogen Activator Antigen and Function

1989 ◽  
Vol 61 (02) ◽  
pp. 289-293 ◽  
Author(s):  
Johann Wojta ◽  
Bernd R Binder ◽  
Kurt Huber ◽  
Richard L Hoover
Keyword(s):  
Thrombolytic Therapy ◽  
Plasminogen Activator ◽  
Microtiter Plate ◽  
Assay System ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Coefficients Of Variation ◽  
Antigen Determination ◽  
And Function

SummaryA combined assay for urokinase type plasminogen activator (u-PA) activity and antigen determination in plasma samples is described. This assay is based on binding of u-PA to an antibody immobilized on a microtiter plate followed by determination of the enzymatic activity of the bound u-PA. Thereafter bound u-PA antigen can be quantified by means of a specific peroxidase labelled monoclonal antibody against u-PA. By use of this assay system u-PA activity and antigen can be determined with lower detection limits of 0.08 IU/ml and 1.0 ng/ml, respectively, and intraassay as well as interassay coefficients of variation of 10% and 12% for activity and 5% and 7% for antigen determinations, respectively. Normal plasma levels of u-PA antigen could be determined to be 1.88 nglml ± 0.61. Furthennore, this assay system allows specific quantification of u-PA antigen and activity during thrombolytic therapy.

scholarly journals uPA deficiency exacerbates muscular dystrophy in MDX mice

2007 ◽  
Vol 178 (6) ◽  
pp. 1039-1051 ◽  
Author(s):  
Mònica Suelves ◽  
Berta Vidal ◽  
Antonio L. Serrano ◽  
Marc Tjwa ◽  
Josep Roma ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Inflammatory Cells ◽  
Mdx Mice ◽  
Muscle Dystrophy ◽  
Dystrophic Muscle ◽  
Critical Function ◽  
Upa Receptor ◽  
Muscular Function ◽  
Degenerative Disorder ◽  
Transplantation Experiments

Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy.

scholarly journals MiR-199-3p enhances muscle regeneration and ameliorates aged muscle and muscular dystrophy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Masashi Fukuoka ◽  
Hiromi Fujita ◽  
Kosumo Numao ◽  
Yasuko Nakamura ◽  
Hideo Shimizu ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Muscle Regeneration ◽  
Myogenic Differentiation ◽  
Aging Effect ◽  
Mdx Mice ◽  
Circulating Mirnas ◽  
Aged Mice ◽  
Age Related ◽  
A Cell

AbstractParabiosis experiments suggest that molecular factors related to rejuvenation and aging circulate in the blood. Here, we show that miR-199-3p, which circulates in the blood as a cell-free miRNA, is significantly decreased in the blood of aged mice compared to young mice; and miR-199-3p has the ability to enhance myogenic differentiation and muscle regeneration. Administration of miR-199 mimics, which supply miR-199-3p, to aged mice resulted in muscle fiber hypertrophy and delayed loss of muscle strength. Systemic administration of miR-199 mimics to mdx mice, a well-known animal model of Duchenne muscular dystrophy (DMD), markedly improved the muscle strength of mice. Taken together, cell-free miR-199-3p in the blood may have an anti-aging effect such as a hypertrophic effect in aged muscle fibers and could have potential as a novel RNA therapeutic for DMD as well as age-related diseases. The findings provide us with new insights into blood-circulating miRNAs as age-related molecules.

Sign in / Sign up

Export Citation Format

Share Document