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BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation.

ABSTRACT: In skeletal muscle, brain-derived neurotrophic factor (BDNF) has long been thought to serve as a retrograde trophic factor for innervating motor neurons throughout their lifespan. However, its localization in mature muscle fibers has remained elusive. Given the postulated roles of BDNF in skeletal muscle, we performed a series of complementary experiments aimed at defining the localization of BDNF and its transcripts in adult muscle. By reverse transcription-PCR, in situ hybridization, and immunofluorescence, we show that BDNF, along with the receptor p75NTR, is not expressed at significant levels within mature myofibers and that it does not accumulate preferentially within subsynaptic regions of neuromuscular junctions. Interestingly, expression of BDNF correlated with that of Pax3, a marker of muscle progenitor cells, in several different adult skeletal muscles. Additionally, BDNF was expressed in Pax7+ satellite cells where it colocalized with p75NTR. In complementary cell culture experiments, we detected high levels of BDNF and p75NTR in myoblasts. During myogenic differentiation, expression of BDNF became drastically reduced. Using small interfering RNA (siRNA) technology to knock down BDNF expression, we demonstrate enhanced myogenic differentiation of myoblasts. This accelerated rate of myogenic differentiation seen in myoblasts expressing BDNF siRNA was normalized by administration of recombinant BDNF. Collectively, these findings show that BDNF plays an important regulatory function during myogenic differentiation. In addition, the expression of BDNF in satellite cells is coherent with the notion that BDNF serves a key role in maintaining the population of muscle progenitors in adult muscle.

SUBMITTER: Mousavi K

PROVIDER: S-EPMC6675269 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation.

Mousavi Kambiz K Jasmin Bernard J BJ

The Journal of neuroscience : the official journal of the Society for Neuroscience 20060501 21

In skeletal muscle, brain-derived neurotrophic factor (BDNF) has long been thought to serve as a retrograde trophic factor for innervating motor neurons throughout their lifespan. However, its localization in mature muscle fibers has remained elusive. Given the postulated roles of BDNF in skeletal muscle, we performed a series of complementary experiments aimed at defining the localization of BDNF and its transcripts in adult muscle. By reverse transcription-PCR, in situ hybridization, and immun ...[more]

PMID: 16723531

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Project description:BackgroundSarcopenia is a common and progressive skeletal muscle disorder characterized by atrophic muscle fibres and contractile dysfunction. Accumulating evidence shows that the number and function of satellite cells (SCs) decline and become impaired during ageing, which may contribute to impaired regenerative capacity. A series of myokines/small extracellular vesicles (sEVs) released from muscle fibres regulate metabolism in muscle and extramuscular tissues in an autocrine/paracrine/endocrine manner during muscle atrophy. It is still unclear whether myokines/sEVs derived from muscle fibres can affect satellite cell function during ageing.MethodsAged mice were used to investigate changes in the myogenic capacity of SCs during ageing-induced muscle atrophy. The effects of atrophic myotube-derived sEVs on satellite cell differentiation were investigated by biochemical methods and immunofluorescence staining. Small RNA sequencing was performed to identify differentially expressed sEV microRNAs (miRNAs) between the control myotubes and atrophic myotubes. The target genes of the miRNA were predicted by bioinformatics analysis and verified by luciferase activity assays. The effects of identified miRNA on the myogenic capacity of SCs in vivo were investigated by intramuscular injection of adeno-associated virus (AAV) to overexpress or silence miRNA in skeletal muscle.ResultsOur study showed that the myogenic capacity of SCs was significantly decreased (50%, n = 6, P < 0.001) in the tibialis anterior muscle of aged mice. We showed that atrophic myotube-derived sEVs inhibited satellite cell differentiation in vitro (n = 3, P < 0.001) and in vivo (35%, n = 6, P < 0.05). We also found that miR-690 was the most highly enriched miRNA among all the screened sEV miRNAs in atrophic myotubes [Log2 (Fold Change) = 7, P < 0.001], which was verified in the atrophic muscle of aged mice (threefold, n = 6, P < 0.001) and aged men with mean age of 71 ± 5.27 years (2.8-fold, n = 10, P < 0.001). MiR-690 can inhibit myogenic capacity of SCs by targeting myocyte enhancer factor 2, including Mef2a, Mef2c and Mef2d, in vitro (n = 3, P < 0.05) and in vivo (n = 6, P < 0.05). Specific silencing of miR-690 in the muscle can promote satellite cell differentiation (n = 6, P < 0.001) and alleviate muscle atrophy in aged mice (n = 6, P < 0.001).ConclusionsOur study demonstrated that atrophic muscle fibre-derived sEV miR-690 may inhibit satellite cell differentiation by targeting myocyte enhancer factor 2 during ageing.

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BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation.

Publications

BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation.

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