Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment

González‐Sánchez, Jessica; Sánchez‐Temprano, Agustín; Cid‐Díaz, Tania; Pabst‐Fernández, Regina; Mosteiro, Carlos S.; Gallego, Rosalı́a; Nogueiras, Rubén; Casabiell, Xesús; Butler‐Browne, Gillian; Mouly, Vincent; Relova, José Luis; Pazos, Yolanda; Camiña, Jesús P.

doi:10.1002/jcsm.12338

Cited by 10 publications

(14 citation statements)

References 50 publications

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“…A small increase in dystrophin expression is sufficient to reduce levels of biomarkers associated with muscle damage CK, LDH, AST, and ALT are serum enzymes that are elevated in several muscular dystrophies, including DMD, and are widely used in the diagnosis of skeletal muscle injury and damage [29,30]. mdx mice are reported to also have elevated levels of these serum biomarkers compared to WT controls [31,32]. We here confirmed that all four biomarkers were indeed significantly increased in mdx mice treated with the scrambled control compared to WT controls (P < 0.0001) ( Fig.…”

Section: Dosing Results In Higher Dystrophin Levels In Skeletal Mumentioning

confidence: 99%

Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

Datson

Bijl

Janson

et al. 2020

Nucleic Acid Therapeutics

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Duchenne muscular dystrophy (DMD) is a severe childhood muscle disease primarily caused by the lack of functional dystrophin at the muscle fiber membranes. Multiple therapeutic approaches are currently in (pre)clinical development, aimed at restoring expression of (truncated) dystrophin. Key questions in this phase relate to route of drug administration, dose regimen, and levels of dystrophin required to improve muscle function. A series of studies applying antisense oligonucleotides (AONs) in the mdx mouse model for DMD has been reported over the last two decades, claiming a variable range of exon skipping and increased dystrophin levels correlated to some functional improvement. The aim of this study was to compare the efficacy of subcutaneous (SC) versus intravenous (IV) dosing routes of an mdx-specific AON at both the molecular and functional level, using state-of-the-art quantitative technologies, including digital droplet polymerase chain reaction, capillary Western immunoassay, magnetic resonance imaging, and automated kinematic analysis. The majority of all readouts we quantified, both molecular and functional, showed that IV dosing of the AON had a more pronounced beneficial effect than SC dosing in mdx mice. Last, but not least, the more quantitative molecular and functional data obtained in this study suggest that low levels of dystrophin protein of at least 2.5% of wild type may already have a beneficial effect on muscle leakiness and may improve motor performance of mdx mice.

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Section: Dosing Results In Higher Dystrophin Levels In Skeletal Mumentioning

confidence: 99%

Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

Datson

Bijl

Janson

et al. 2020

Nucleic Acid Therapeutics

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“…Similarly, upregulation of utrophin and improvement of the DMD phenotype in mdx mice seems to accompany the reduction of ubiquitin ligase E3 enzymes 51,52 . Utrophin is homologous to dystrophin and also has an affinity for the binding of F‐actin to DGC 53 .…”

Section: Discussionmentioning

confidence: 99%

“…50 Similarly, upregulation of utrophin and improvement of the DMD phenotype in mdx mice seems to accompany the reduction of ubiquitin ligase E3 enzymes. 51,52 Utrophin is homologous to dystrophin and also has an affinity for the binding of F-actin to DGC. 53 Utrophin is upregulated in the mdx mouse, which gives a milder phenotype for this model; however, this upregulation was not observed in patients with DMD.…”

Section: Discussionmentioning

confidence: 99%

Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin‐deficient mdx mice

Micheletto

Hermes

Bertassoli

et al. 2020

Int J Experimental Path

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“…In previous works, we demonstrated the therapeutic potential of the obestatin/GPR39 system, an autocrine/paracrine system, to regulate skeletal muscle repair [26][27][28][29][30]. Obestatin, a 23-amino acid peptide derived from a polypeptide called preproghrelin, exerts an autocrine anabolic function in skeletal muscle to control the myogenic programme through the G protein-coupled receptor GPR39 [26].…”

mentioning

confidence: 99%

“…In cell transplantation therapy, obestatin not only enhances the e ciency of engraftment but also facilitates an even distribution of myoblasts within the host muscle by enhancing migration [31]. Furthermore, obestatin ameliorate the Duchenne muscular dystrophy phenotype [30]. Interestingly enough, obestatin triggers an up-regulation of the neuromuscular junction (NMJ) genes.…”

mentioning

confidence: 99%

Obestatin signaling controls Schwann cells and axonal transport to counteract neuromuscular synaptic loss in skeletal muscle

Camiña¹,

Sánchez‐Temprano²,

Leal‐López³

et al. 2020

Preprint

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Background. Injuries to the peripheral nerve system are common conditions, with broad spectrum of symptoms depending on the impaired nerves and severity of damage. Although peripheral nervous system retains a remarkable ability for regeneration, it is estimated that less than ten percent of patients fully recover function after nerve injury and the available treatments remain suboptimal. Here, we identify a role for the obestatin/GPR39 system in the regulation of the Schwann cell plasticity as well as in the preservation of neuromuscular synapses in the course of nerve repair. Methods. Utilizing a compression model of sciatic nerve injury, axonotmesis, we assessed the obestatin-related regenerative response in the peripheral nerve system. The role of the obestatin/GPR39 system was further evaluated on immortalized rat Schwann cells, IFRS1, and the model of neuronal differentiation, PC12 cells. The interactions between SCs and neurons was evaluated using a co-culture system that combine the SC cell line IFRS1 and the NGF-primed PC12. Results. Obestatin signaling directs proliferation and migration of Schwann cells that sustain axonal regrowth and later remyelinate regenerated axons. We provide evidence supporting the preservation of skeletal muscle by the maintenance of neuromuscular synapses through the axonal regulation of calpain-calpastatin proteolytic system. This encompasses the control of skeletal muscle homeostasis by regulation of the ubiquitin proteasome system and the autophagy machinery. Conclusions. These results provide important insights into how the obestatin/GPR39 system promotes nerve repair through integration of multiple molecular cues of neuron-Schwann cells crosstalk aimed to promote axon growth and guide axons back to their targets.

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Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment

Cited by 10 publications

References 50 publications

Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin‐deficient mdx mice

Obestatin signaling controls Schwann cells and axonal transport to counteract neuromuscular synaptic loss in skeletal muscle

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