Enhanced pro-BDNF-p75NTR pathway activity in denervated skeletal muscle

Aby, Katherine; Antony, Ryan; Eichholz, Mary; Srinivasan, Rekha; Li, Yifan

doi:10.1016/j.lfs.2021.120067

Cited by 10 publications

(7 citation statements)

References 44 publications

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“…This contrast may be associated with changes in proneurotrophin activity in mature motor synapses. These include a decrease in proBDNF expression (compared with the post-denervation stage), changes in the expression of receptors, and intra- and extra-cellular enzymes required for proBDNF cleavage, both in muscle fibers and in motor nerve terminals ( Meeker and Williams, 2014 ; Aby et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, these peptides had opposite effects on ACh release and stabilization of synapses due to activation of different presynaptic receptors – TrkB for BDNF and p75 for proBDNF ( Je et al, 2012 , 2013 ). An acute increase in the level of proBDNF and p75 receptors expression was recently revealed in mature mouse skeletal muscle in response to its denervation ( Aby et al, 2021 ). However, the role of this upregulation of proBDNF and the range of its retrograde effects during the period of muscle reinnervation and synaptic formation were not studied yet.…”

Section: Introductionmentioning

confidence: 98%

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ProBDNF and Brain-Derived Neurotrophic Factor Prodomain Differently Modulate Acetylcholine Release in Regenerating and Mature Mouse Motor Synapses

Bogacheva

Молчанова

Pravdivceva

et al. 2022

Front. Cell. Neurosci.

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The effects of brain-derived neurotrophic factor (BDNF) processing by-products (proBDNF and BDNF prodomain) on the activity of mouse neuromuscular junctions (NMJs) were studied in synapses formed during the reinnervation of extensor digitorum longus muscle (m. EDL) and mature synapses of the diaphragm. The parameters of spontaneous miniature endplate potentials (MEPPs) and evoked endplate potentials (EPPs) were analyzed in presence of each of the BDNF maturation products (both – 1 nM). In newly formed NMJs, proBDNF caused an increase in the resting membrane potential of muscle fibers and a decrease in the frequency of MEPPs, which was prevented by tertiapin-Q, a G-protein-coupled inwardly rectifying potassium channels (GIRK) blocker but not by p75 receptor signaling inhibitor TAT-Pep5. proBDNF had no effect on the parameters of EPPs. BDNF prodomain in newly formed synapses had effects different from those of proBDNF: it increased the amplitude of MEPPs, which was prevented by vesamicol, an inhibitor of vesicular acetylcholine (ACh) transporter; and reduced the quantal content of EPPs. In mature NMJs, proBDNF did not influence MEPPs parameters, but BDNF prodomain suppressed both spontaneous and evoked ACh release: decreased the frequency and amplitude of MEPPs, and the amplitude and quantal content of EPPs. This effect of the BDNF prodomain was prevented by blocking GIRK channels, by TAT-Pep5 or by Rho-associated protein kinase (ROCK) inhibitor Y-27632. At the same time, the BDNF prodomain did not show any inhibitory effects in diaphragm motor synapses of pannexin 1 knockout mice, which have impaired purinergic regulation of neuromuscular transmission. The data obtained suggest that there is a previously unknown mechanism for the acute suppression of spontaneous and evoked ACh release in mature motor synapses, which involves the activation of p75 receptors, ROCK and GIRK channels by BDNF prodomain and requires interaction with metabotropic purinoreceptors. In general, our results show that both the precursor of BDNF and the product of its maturation have predominantly inhibitory effects on spontaneous and evoked ACh release in newly formed or functionally mature neuromuscular junctions, which are mainly opposite to the effects of BDNF. The inhibitory influences of both proteins related to brain neurotrophin are mediated via GIRK channels of mouse NMJs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

ProBDNF and Brain-Derived Neurotrophic Factor Prodomain Differently Modulate Acetylcholine Release in Regenerating and Mature Mouse Motor Synapses

Bogacheva

Молчанова

Pravdivceva

et al. 2022

Front. Cell. Neurosci.

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“…Of these, CEBPD has been reported to be a biomarker for amyotrophic lateral sclerosis ( Sun et al, 2022 ). BDNF can improve muscle atrophy by promoting nerve regeneration ( Yongguang et al, 2022 ) and is a target for skeletal muscle inflammation ( Aby et al, 2021 ). TP53INP2 is a key regulator of skeletal muscle ( Sala and Zorzano, 2015 ) and regulates muscle atrophy due to cancer cachexia by activating autophagy ( Penna et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics, network pharmacology, and artificial intelligence to predict the mechanism of celastrol against muscle atrophy caused by colorectal cancer

Zhang

2022

Front. Genet.

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Muscle atrophy due to colorectal cancer severely reduces the quality of life and survival time of patients. However, the underlying causative mechanisms and therapeutic agents are not well understood. The aim of this study was to screen and identify the microRNA (miRNA)–mRNA regulatory network and therapeutic targets of celastrol in colorectal cancer causing muscle atrophy via blood exosomes. Datasets were downloaded from the Gene Expression Omnibus online database. Differential expression analysis was first performed using the blood exosome dataset GSE39833 from colorectal cancer and normal humans to identify differentially expressed (DE) miRNAs, and then, transcriptional enrichment analysis was performed to identify important enriched genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed by FunRich software. Using the muscle atrophy sample GSE34111, the DE mRNAs in the muscle atrophy sample were analyzed, a regulatory network map was established based on miRNA‒mRNA regulatory mechanisms, further GO and KEGG enrichment analyses were performed for the DE genes in muscle atrophy via Cytoscape’s ClueGO plug-in, and the network pharmacology pharmacophore analysis method was used to analyze the celastrol therapeutic targets, taking intersections to find the therapeutic targets of celastrol, using the artificial intelligence AlphaFold2 to predict the protein structures of the key targets, and finally using molecular docking to verify whether celastrol and the target proteins can be successfully docked. A total of 82 DE miRNAs were obtained, and the top 10 enriched target genes were identified. The enrichment of the 82 miRNAs showed a close correlation with muscle atrophy, and 332 DE mRNAs were found by differential expression analysis in muscle atrophy samples, among which 44 mRNA genes were involved in miRNA‒mRNA networks. The DE genes in muscle atrophy were enriched for 30 signaling pathways, and 228 target genes were annotated after pharmacophore target analysis. The NR1D2 gene, the target of treatment, was found by taking intersections, the protein structure of this target was predicted by AlphaFold2, and the structure was successfully docked and validated using molecular docking. In our present study, colorectal cancer likely enters the muscle from blood exosomes and regulates skeletal muscle atrophy through miRNA‒mRNA regulatory network mechanisms, and celastrol treats muscle through NR1D2 in the miRNA‒mRNA regulatory network.

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“…Studies on BDNF’s function and expression regulation in various non-CNS tissues are fragmented, and inconsistent results are frequently reported, possibly due to the distinct and opposite functions of BDNF isoforms, especially in gene knockout studies where both pro-BDNF and mBDNF are depleted. For instance, ablating the Bdnf gene in the Skm mitigates the denervation-induced muscle atrophy but overexpressing Bdnf also has an ameliorating effect on the defective muscle function in neuromuscular disease [ 123 , 124 ]. Moreover, the lack of precise tools significantly impedes the result interpretation and conclusion to be made.…”

Section: Unresolved Questionsmentioning

confidence: 99%

“…Studies on BDNF's function expression regulation in various non-CNS tissues are fragmented, and inconsistent re are frequently reported, possibly due to the distinct and opposite functions of B isoforms, especially in gene knockout studies where both pro-BDNF and mBDNF depleted. For instance, ablating the Bdnf gene in the Skm mitigates the denerva induced muscle atrophy but overexpressing Bdnf also has an ameliorating effect o defective muscle function in neuromuscular disease [123,124]. Moreover, the lac precise tools significantly impedes the result interpretation and conclusion to be m An obvious example is the non-specificity of antibodies that recognize BDNF and T Because most commercially available antibodies show a certain degree of cross-react with other proteins, it is difficult to accurately determine the cell types that express B and TrkB in tissue or serum.…”

Section: Unresolved Questionsmentioning

confidence: 99%

Is Brain-Derived Neurotrophic Factor a Metabolic Hormone in Peripheral Tissues?

Chan

2022

Biology

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Brain-derived neurotrophic factor (BDNF) is an important growth factor in the central nervous system. In addition to its well-known activities in promoting neuronal survival, neuron differentiation, and synaptic plasticity, neuronal BDNF also regulates energy homeostasis by modulating the hypothalamus’s hormonal signals. In the past decades, several peripheral tissues, including liver, skeletal muscle, and white adipose tissue, were demonstrated as the active sources of BDNF synthesis in response to different metabolic challenges. Nevertheless, the functions of BDNF in these tissues remain obscure. With the use of tissue-specific Bdnf knockout animals and the availability of non-peptidyl BDNF mimetic, increasing evidence has reported that peripheral tissues-derived BDNF might play a significant role in maintaining systemic metabolism, possibly through the regulation of mitochondrial dynamics in the various tissues. This article reviews the autocrine/paracrine/endocrine functions of BDNF in non-neuronal tissues and discusses the unresolved questions about BDNF’s function.

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Enhanced pro-BDNF-p75NTR pathway activity in denervated skeletal muscle

Cited by 10 publications

References 44 publications

ProBDNF and Brain-Derived Neurotrophic Factor Prodomain Differently Modulate Acetylcholine Release in Regenerating and Mature Mouse Motor Synapses

ProBDNF and Brain-Derived Neurotrophic Factor Prodomain Differently Modulate Acetylcholine Release in Regenerating and Mature Mouse Motor Synapses

Integrated bioinformatics, network pharmacology, and artificial intelligence to predict the mechanism of celastrol against muscle atrophy caused by colorectal cancer

Is Brain-Derived Neurotrophic Factor a Metabolic Hormone in Peripheral Tissues?

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