Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice

The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:β1,4- N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcβ1,4[NeuAc(orGc)α2, 3]Galβ1,4GlcNAcβ-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.

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Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.082613599 ◽

2002 ◽

Vol 99 (8) ◽

pp. 5616-5621 ◽

Cited By ~ 101

Author(s):

H. H. Nguyen ◽

V. Jayasinha ◽

B. Xia ◽

K. Hoyte ◽

P. T. Martin

Keyword(s):

Skeletal Muscle ◽

T Cell ◽

Muscular Dystrophy ◽

Cytotoxic T Cell ◽

Mdx Mice

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Deficiency of MMP-10 Aggravates the Diseased Phenotype of Aged Dystrophic Mice

10.20944/preprints202111.0017.v1 ◽

2021 ◽

Author(s):

Arantxa Baraibar Churio ◽

Miriam Bobadilla ◽

Neira Sainz ◽

Florencio JD Machado ◽

Josune Orbe ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Hind Limb ◽

Survival Rates ◽

Muscle Pathology ◽

Mdx Mice ◽

Chronic Inflammatory Response ◽

Cardiac Muscles ◽

Dystrophic Mice

Matrix metalloproteinases have been implicated in muscular dystrophy progression and recent studies described the role of MMP-10 in skeletal muscle pathology of young dystrophic mice. Nevertheless, its implication in dystrophin deficient hearts is still missing. Here, we aimed at investigating MMP-10 implication in severe muscular dystrophic progression and characterize MMP-10 loss in skeletal and cardiac muscles of aged dystrophic mice. We examined the histopathological effect of MMP-10 ablation in aged mdx mice, both in the hind limb muscles and heart tissues. We have found that MMP-10 loss compromises survival rates of aged mdx mice, with skeletal and cardiac muscles developing a chronic inflammatory response. Our findings indicate that MMP-10 is implicated in severe muscular dystrophy progression, identifying a new area of investigation that could lead to future therapies for dystrophic muscles.

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Deficiency of MMP-10 Aggravates the Diseased Phenotype of Aged Dystrophic Mice

Life ◽

10.3390/life11121398 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1398

Author(s):

Arantxa Baraibar-Churio ◽

Míriam Bobadilla ◽

Florencio J. D. Machado ◽

Neira Sáinz ◽

Carmen Roncal ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Hind Limb ◽

Survival Rates ◽

Muscle Pathology ◽

Mdx Mice ◽

Chronic Inflammatory Response ◽

Cardiac Muscles ◽

Dystrophic Mice

Matrix metalloproteinases (MMPs) have been implicated in the progression of muscular dystrophy, and recent studies have reported the role of MMP-10 in skeletal muscle pathology of young dystrophic mice. Nevertheless, its involvement in dystrophin-deficient hearts remains unexplored. Here, we aimed to investigate the involvement of MMP-10 in the progression of severe muscular dystrophy and to characterize MMP-10 loss in skeletal and cardiac muscles of aged dystrophic mice. We examined the histopathological effect of MMP-10 ablation in aged mdx mice, both in the hind limb muscles and heart tissues. We found that MMP-10 loss compromises survival rates of aged mdx mice, with skeletal and cardiac muscles developing a chronic inflammatory response. Our findings indicate that MMP-10 is implicated in severe muscular dystrophy progression, thus identifying a new area of research that could lead to future therapies for dystrophic muscles.

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Animal Models for Muscular Dystrophy Show Different Patterns of Sarcolemmal Disruption

The Journal of Cell Biology ◽

10.1083/jcb.139.2.375 ◽

1997 ◽

Vol 139 (2) ◽

pp. 375-385 ◽

Cited By ~ 340

Author(s):

Volker Straub ◽

Jill A. Rafael ◽

Jeffrey S. Chamberlain ◽

Kevin P. Campbell

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Animal Models ◽

Transgenic Mice ◽

Evans Blue ◽

Muscle Fibers ◽

Congenital Muscular Dystrophy ◽

Mdx Mice ◽

Skeletal Muscle Fibers

Genetic defects in a number of components of the dystrophin–glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Evans blue, a low molecular weight diazo dye, does not cross into skeletal muscle fibers in normal mice. In contrast, mdx mice, a dystrophin-deficient animal model for Duchenne muscular dystrophy, showed significant Evans blue accumulation in skeletal muscle fibers. We also studied Evans blue dispersion in transgenic mice bearing different dystrophin mutations, and we demonstrated that cytoskeletal and sarcolemmal attachment of dystrophin might be a necessary requirement to prevent serious fiber damage. The extent of dye incorporation in transgenic mice correlated with the phenotypic severity of similar dystrophin mutations in humans. We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its milder allelic variant, the dy2J/dy2J mouse, animal models for congenital muscular dystrophy. Surprisingly, these mice, which have defects in the laminin α2-chain, an extracellular ligand of the DGC, showed little Evans blue accumulation in their skeletal muscles. Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.

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Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

JRSM Cardiovascular Disease ◽

10.1177/2048004019879581 ◽

2019 ◽

Vol 8 ◽

pp. 204800401987958

Author(s):

HR Spaulding ◽

C Ballmann ◽

JC Quindry ◽

MB Hudson ◽

JT Selsby

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Gene Mutations ◽

Dystrophin Gene ◽

Mdx Mice ◽

Dystrophin Deficiency ◽

Muscle Wasting Disease ◽

Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

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Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00107.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E876-E888 ◽

Cited By ~ 193

Author(s):

Suzanne Reisz-Porszasz ◽

Shalender Bhasin ◽

Jorge N. Artaza ◽

Ruoqing Shen ◽

Indrani Sinha-Hikim ◽

...

Keyword(s):

Skeletal Muscle ◽

Transgenic Mice ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Fluorescent Protein ◽

Male Mice ◽

Wild Type ◽

Specific Expression ◽

Muscle Weight ◽

Myostatin Gene

Mutations in the myostatin gene are associated with hypermuscularity, suggesting that myostatin inhibits skeletal muscle growth. We postulated that increased tissue-specific expression of myostatin protein in skeletal muscle would induce muscle loss. To investigate this hypothesis, we generated transgenic mice that overexpress myostatin protein selectively in the skeletal muscle, with or without ancillary expression in the heart, utilizing cDNA constructs in which a wild-type (MCK/Mst) or mutated muscle creatine kinase (MCK-3E/Mst) promoter was placed upstream of mouse myostatin cDNA. Transgenic mice harboring these MCK promoters linked to enhanced green fluorescent protein (EGFP) expressed the reporter protein only in skeletal and cardiac muscles (MCK) or in skeletal muscle alone (MCK-3E). Seven-week-old animals were genotyped by PCR of tail DNA or by Southern blot analysis of liver DNA. Myostatin mRNA and protein, measured by RT-PCR and Western blot, respectively, were significantly higher in gastrocnemius, quadriceps, and tibialis anterior of MCK/Mst-transgenic mice compared with wild-type mice. Male MCK/Mst-transgenic mice had 18–24% lower hind- and forelimb muscle weight and 18% reduction in quadriceps and gastrocnemius fiber cross-sectional area and myonuclear number (immunohistochemistry) than wild-type male mice. Male transgenic mice with mutated MCK-3E promoter showed similar effects on muscle mass. However, female transgenic mice with either type of MCK promoter did not differ from wild-type controls in either body weight or skeletal muscle mass. In conclusion, increased expression of myostatin in skeletal muscle is associated with lower muscle mass and decreased fiber size and myonuclear number, decreased cardiac muscle mass, and increased fat mass in male mice, consistent with its role as an inhibitor of skeletal muscle mass. The mechanism of gender specificity remains to be clarified.

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Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins

Cell ◽

10.1016/0092-8674(94)90177-5 ◽

1994 ◽

Vol 76 (1) ◽

pp. 117-129 ◽

Cited By ~ 233

Author(s):

David Westaway ◽

Stephen J. DeArmond ◽

Juliana Cayetano-Canlas ◽

Darlene Groth ◽

Dallas Foster ◽

...

Keyword(s):

Skeletal Muscle ◽

Central Nervous System ◽

Nervous System ◽

Transgenic Mice ◽

Peripheral Nerves ◽

Prion Proteins ◽

Wild Type ◽

The Central Nervous System

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Calcium-binding proteins in skeletal muscles of the mdx mice: potential role in the pathogenesis of Duchenne muscular dystrophy

International Journal of Experimental Pathology ◽

10.1111/j.1365-2613.2009.00688.x ◽

2010 ◽

Vol 91 (1) ◽

pp. 63-71 ◽

Cited By ~ 15

Author(s):

Adriana Pertille ◽

Candida Luiza Tonizza de Carvalho ◽

Cintia Yuri Matsumura ◽

Humberto Santo Neto ◽

Maria Julia Marques

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Calcium Binding ◽

Skeletal Muscles ◽

Binding Proteins ◽

Potential Role ◽

Calcium Binding Proteins ◽

Mdx Mice

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Rskα-actin/hIGF-1 transgenic mice with increased IGF-I in skeletal muscle and blood: Impact on regeneration, denervation and muscular dystrophy

Growth Hormone & IGF Research ◽

10.1016/j.ghir.2005.11.003 ◽

2006 ◽

Vol 16 (3) ◽

pp. 157-173 ◽

Cited By ~ 16

Author(s):

T. Shavlakadze ◽

J.M. Boswell ◽

D.W. Burt ◽

E.A. Asante ◽

F.M. Tomas ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Transgenic Mice ◽

Igf I

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Soluble guanylate cyclase stimulation mitigates skeletal and cardiac muscle dysfunction in a mdx model of Duchenne muscular dystrophy

10.1101/2021.02.14.431156 ◽

2021 ◽

Author(s):

Ling Zhang ◽

Yuanyuan Xu ◽

Keyvan Yousefi ◽

Camila I. Irion ◽

Roger A. Alvarez ◽

...

Keyword(s):

Nitric Oxide ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Signal Propagation ◽

Guanosine Monophosphate ◽

Muscle Pathology ◽

Mdx Mice

AbstractThe impairment of neuronal nitric oxide synthase (nNOS) signaling contributes to disease pathology in the muscle wasting disorder Duchenne muscular dystrophy (DMD). nNOS signal propagation occurs through nitric oxide sensitive soluble guanylate cyclase (sGC), a critical source of cyclic guanosine monophosphate (cGMP) in muscle. Although both nNOS and sGC activity are impaired in DMD patients, little is known about sGC as a therapeutic target. In this study, we tested the hypothesis that stimulating sGC activity with the allosteric agonist BAY41-8543 mitigates striated muscle pathology in the mdx4cv mouse model of DMD. In contrast to DMD patients, mdx mice exhibited greater basal sGC activity than wild type controls with preservation of cGMP levels due partly to upregulation of sGC in some muscles. Stimulating sGC activity in mdx mice with BAY41-8543 substantially reduced skeletal muscle damage, macrophage densities and inflammation and significantly increased resistance to contraction-induced fatigue. BAY41-8543 also enhanced in vivo diaphragm function while reducing breathing irregularities suggesting improved respiratory function. BAY41-8543 attenuated cardiac hypertrophic remodeling, fibrosis and diastolic dysfunction including left atrium enlargement in aged mdx mice. Overall, sGC stimulation significantly mitigated skeletal and cardio-respiratory dysfunction in mdx4cv mice. Importantly, this study provides compelling pre-clinical evidence supporting sGC as a novel target in DMD and the repurposing of FDA-approved sGC stimulators, such as riociguat and veraciguat, as a novel therapeutic approach for DMD.

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