Injection of a Soluble Fragment of Neural Agrin (NT-1654) Considerably Improves the Muscle Pathology Caused by the Disassembly of the Neuromuscular Junction

Hettwer, Stefan; Lin, Shuo; Kucsera, Stefan; Haubitz, Monika; Oliveri, Filippo; Fariello, Ruggero G.; Rüegg, Markus A.; Vrijbloed, Jan W.

doi:10.1371/journal.pone.0088739

Cited by 48 publications

(61 citation statements)

References 40 publications

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“…Evidence indicating that agrin and other integral components of the NMJ act to repair age-related damages comes from studies assessing their therapeutic potential following injury and in disease. Following sciatic nerve crush surgery in young animals, introduction of biologically active agrin fragments into skeletal muscles accelerates the rate of NMJ reformation [68]. Dok-7 has also been shown to repair damaged NMJs.…”

Section: Lifestyle and Molecular Factors That Preserve The Nmj Intmentioning

confidence: 99%

NMJ maintenance and repair in aging

Taetzsch

Valdez

2018

Current Opinion in Physiology

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As the final output of the somatic nervous system, the neuromuscular junction (NMJ) is essential for all voluntary movements. The NMJ is also necessary for connected cells to function and survive. Because of this central role, much effort has been devoted to understanding the effects of aging, diseases, and injuries on the NMJ. These efforts have revealed a close relationship between aberrant changes at NMJs and its three cellular components - the presynaptic site on motor axons, the postsynaptic region on muscle fibers and perisynaptic Schwann cells. Here, we review the morphological and molecular changes associated with aging NMJs in rodents and humans. We also provide an overview of factors with potential roles in maintaining and repairing adult and aged NMJs.

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Section: Lifestyle and Molecular Factors That Preserve The Nmj Intmentioning

confidence: 99%

NMJ maintenance and repair in aging

Taetzsch

Valdez

2018

Current Opinion in Physiology

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“…Plasma CAFs have been found to be elevated in elderly humans, suggesting that they may be a useful biomarker of sarcopenia arising from age-associated neuromuscular decline [15–18]. Interestingly, injection of an agrin biologic (NT-1654) was able to reverse the sarcopenia-like phenotype in SARCO mice, suggesting that modulating the agrin–LRP4–MuSK pathway may be a novel therapeutic strategy in the treatment of age-related muscle wasting, neuromuscular disease and associated muscle dysfunction [20]. To our knowledge, the present study is the first report of the modulation of muscle agrin levels as a result of nutritional supplementation.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, overexpression of neurotrypsin resulted in a precocious sarcopenic phenotype that was characterised by weakness, NMJ fragmentation and pathological muscle abnormalities (termed SARCO mice) [19]. Administration of a recombinant neurotrypsin-resistant form of agrin has been shown to improve muscle pathology by minimising the disassembly of the NMJ in SARCO mice [20]. Therefore, modulation of muscle agrin signalling and/or NMJs may be a novel treatment of sarcopenia and neuromuscular disease.…”

Section: Introductionmentioning

confidence: 99%

Dietary supplementation with bovine-derived milk fat globule membrane lipids promotes neuromuscular development in growing rats

et al. 2017

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BackgroundThe milk fat globule membrane (MFGM) is primarily composed of polar phospho- and sphingolipids, which have established biological effects on neuroplasticity. The present study aimed to investigate the effect of dietary MFGM supplementation on the neuromuscular system during post-natal development.MethodsGrowing rats received dietary supplementation with bovine-derived MFGM mixtures consisting of complex milk lipids (CML), beta serum concentrate (BSC) or a complex milk lipid concentrate (CMLc) (which lacks MFGM proteins) from post-natal day 10 to day 70.ResultsSupplementation with MFGM mixtures enriched in polar lipids (BSC and CMLc, but not CML) increased the plasma phosphatidylcholine (PC) concentration, with no effect on plasma phosphatidylinositol (PI), phosphatidylethanolamine (PE), phosphatidylserine (PS) or sphingomyelin (SM). In contrast, muscle PC was reduced in rats receiving supplementation with both BSC and CMLc, whereas muscle PI, PE, PS and SM remained unchanged. Rats receiving BSC and CMLc (but not CML) displayed a slow-to-fast muscle fibre type profile shift (MyHCI → MyHCIIa) that was associated with elevated expression of genes involved in myogenic differentiation (myogenic regulatory factors) and relatively fast fibre type specialisation (Myh2 and Nfatc4). Expression of neuromuscular development genes, including nerve cell markers, components of the synaptogenic agrin–LRP4 pathway and acetylcholine receptor subunits, was also increased in muscle of rats supplemented with BSC and CMLc (but not CML).ConclusionsThese findings demonstrate that dietary supplementation with bovine-derived MFGM mixtures enriched in polar lipids can promote neuromuscular development during post-natal growth in rats, leading to shifts in adult muscle phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-017-0161-y) contains supplementary material, which is available to authorized users.

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“…1) was tested with respect to its therapeutic efficacy [24]. Subcutaneous injection of the compound into neurotrypsinoverexpressing mice largely rescued their sarcopenic phenotype, which includes severe precocious muscle wasting, weakness, and neuromuscular junction degeneration.…”

Section: Introductionmentioning

confidence: 99%

Neuromuscular junction degeneration in muscle wasting

Rudolf

Deschenes²,

Sandri³

2016

Current Opinion in Clinical Nutrition and Metabolic Care

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Purpose of review Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and clinical relevance of maintaining the neuromuscular junction to counteract muscle wasting resulting from aging or neural disease/damage. Recent findings Activity-dependent regulation of autophagy, the agrin-MuSK-Lrp4 signaling axis, and sympathetic modulation are principal mechanisms involved in stabilizing the neuromuscular junction. These findings are derived from several animal models and were largely confirmed by human gene expression analysis as well as insights from rare neuromuscular diseases such as amyotrophic lateral sclerosis and congenital myasthenic syndromes. Based on these insights, agrin-derived fragments are currently being evaluated as biomarkers for age-related muscle wasting. Tuning of autophagy, of the agrin pathway, and of sympathetic input are being studied as clinical treatment of muscle wasting disorders. Summary Basic research has revealed that maintenance of neuromuscular junctions and a few signaling pathways are important in the context of age-dependent and other forms of muscle wasting. These findings have recently started to enter clinical practice, but further research needs to substantiate and refine our knowledge.

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Injection of a Soluble Fragment of Neural Agrin (NT-1654) Considerably Improves the Muscle Pathology Caused by the Disassembly of the Neuromuscular Junction

Cited by 48 publications

References 40 publications

NMJ maintenance and repair in aging

NMJ maintenance and repair in aging

Dietary supplementation with bovine-derived milk fat globule membrane lipids promotes neuromuscular development in growing rats

Neuromuscular junction degeneration in muscle wasting

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