RGMa can induce skeletal muscle cell hyperplasia via association with neogenin signalling pathway

Costa, Alinne C.; Copola, Aline Gonçalves Lio; Souza, Clara Carvalho E; Nogueira, Júlia Meireles; Silva, Gerluza Aparecida Borges; Jorge, Érika Cristina

doi:10.1007/s11626-021-00555-9

Cited by 5 publications

(5 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mef2 can also act as a nodal point for remodeling programs in metabolic gene expression, fiber-type switching, and skeletal muscle regeneration [58,59,61]. Mef2a upregulation can also contribute to terminal differentiation and myoblast fusion, which is also consistent with the present GO term analysis and with the RGMa muscle phenotype [25,38]. Mef2a, Mef2c, and Mef2d deleted in combination in satellite cells abolished skeletal muscle regeneration after cardiotoxin injury [59].…”

Section: Rgma Treatment Modulated the Expression Of Muscle Hypertroph...supporting

confidence: 86%

“…Notably, both signaling pathways seem to be active in skeletal muscle cells, inducing similar phenotypes in controlling the cell size, but these effects were never investigated in the context of having RGMa as a possible ligand. Using RGMa recombinant proteins in C2C12 cells, we could not clearly elucidate if RGMa effects were induced via neogenin and/or BMP signaling pathways, possibly because these receptors do not have RGMa as an exclusive ligand [38]. For this reason, in this work, the transcriptome of C2C12 cells was sequenced after being treated with RGMa recombinant protein during the late differentiation stage to detect the transcripts that had their expression modulated by this axon guidance molecule during the differentiation of skeletal muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…1A). DM was then replaced with fasting medium (FM), composed of DMEM supplemented with 0.2% FBS, and cells were incubated at the same conditions for 3 h. Subsequently, C2C12 were treated with 50 ng/ml mouse RGMa recombinant protein (R&D Systems) in FM and incubated for an additional 48 h, as previously described [38]. The recombinant protein was omitted in the control samples.…”

Section: Rgma Recombinant Protein Treatmentmentioning

confidence: 99%

See 2 more Smart Citations

Transcriptomic characterization of the molecular mechanisms induced by RGMa during skeletal muscle nuclei accretion and hypertrophy

et al. 2022

Self Cite

View full text Add to dashboard Cite

Background The repulsive guidance molecule a (RGMa) is a GPI-anchor axon guidance molecule first found to play important roles during neuronal development. RGMa expression patterns and signaling pathways via Neogenin and/or as BMP coreceptors indicated that this axon guidance molecule could also be working in other processes and diseases, including during myogenesis. Previous works from our research group have consistently shown that RGMa is expressed in skeletal muscle cells and that its overexpression induces both nuclei accretion and hypertrophy in muscle cell lineages. However, the cellular components and molecular mechanisms induced by RGMa during the differentiation of skeletal muscle cells are poorly understood. In this work, the global transcription expression profile of RGMa-treated C2C12 myoblasts during the differentiation stage, obtained by RNA-seq, were reported. Results RGMa treatment could modulate the expression pattern of 2,195 transcripts in C2C12 skeletal muscle, with 943 upregulated and 1,252 downregulated. Among them, RGMa interfered with the expression of several RNA types, including categories related to the regulation of RNA splicing and degradation. The data also suggested that nuclei accretion induced by RGMa could be due to their capacity to induce the expression of transcripts related to ‘adherens junsctions’ and ‘extracellular-cell adhesion’, while RGMa effects on muscle hypertrophy might be due to (i) the activation of the mTOR-Akt independent axis and (ii) the regulation of the expression of transcripts related to atrophy. Finally, RGMa induced the expression of transcripts that encode skeletal muscle structural proteins, especially from sarcolemma and also those associated with striated muscle cell differentiation. Conclusions These results provide comprehensive knowledge of skeletal muscle transcript changes and pathways in response to RGMa.

show abstract

Section: Rgma Treatment Modulated the Expression Of Muscle Hypertroph...supporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Rgma Recombinant Protein Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptomic characterization of the molecular mechanisms induced by RGMa during skeletal muscle nuclei accretion and hypertrophy

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mef2 can also act as a nodal point for remodelling programs in metabolic gene expression, bre-type switching, and skeletal muscle regeneration[59, 60, 62]. Mef2a upregulation can also contribute to terminal differentiation and myoblast fusion, which is also consistent with the present GO term analysis and with the RGMa muscle phenotype[26,39]. Mef2a, Mef2c, and Mef2d deleted in combination in satellite cells abolished skeletal muscle regeneration after cardiotoxin injury [60].Our RNA-seq database suggested other hypertrophic mechanisms that could be regulated by RGMa treatment, including the upregulation of Sirtuin 1 (Sirt1), which is known to regulate protein degradation via FoxO inhibition[63]; the upregulation of Nos1, which interacts with Sirt1 [64]; or the downregulation of genes that promote muscle protein degradation, such as the activating transcription factor 4 (Atf4)[65, 66].…”

supporting

confidence: 81%

“…Notably, both signalling pathways seem to be active in skeletal muscle cells, inducing similar phenotypes in controlling the cell size, but these effects were never investigated in the context of having RGMa as a possible ligand. Using RGMa recombinant proteins in C2C12 cells, we could not clearly elucidate if RGMa effects were induced via neogenin and/or BMP signalling pathways, possibly because these receptors do not have RGMa as an exclusive ligand [39]. For this reason, in this work, the transcriptome of C2C12 cells was sequenced after being treated with RGMa recombinant protein during the late differentiation stage to detect the transcripts that had their expression modulated by this axon guidance molecule during the induction of hypertrophy and hyperplasia of skeletal muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Characterisation of the Molecular Mechanisms Induced by RGMa During Skeletal Muscle Hyperplasia and Hypertrophy

Copola¹,

Santos²,

Coutinho³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Background: The repulsive guidance molecule a (RGMa) is a GPI-anchor axon guidance molecule first found to play important roles during neuronal development. RGMa expression patterns and signalling pathways via Neogenin and/or as BMP coreceptors indicated that this axon guidance molecule could also be working in other processes and diseases, including during myogenesis. Previous works have consistently shown that RGMa is expressed in skeletal muscle cells and that its overexpression induces both nuclei accretion and hypertrophy in muscle cell lineages. However, the cellular components and molecular mechanisms induced by RGMa during the differentiation of skeletal muscle cells are poorly understood. In this work, the global transcription expression profile of RGMa-treated C2C12 myoblasts during the differentiation stage, obtained by RNA-seq, were reported. Results: RGMa treatment could modulate the expression pattern of 2,195 transcripts in C2C12 skeletal muscle, with 943 upregulated and 1,252 downregulated. Among them, RGMa interfered with the expression of several RNA types, including categories related to the regulation of RNA splicing and degradation. The data also suggested that RGMa hyperplasia effects could be due to their capacity to induce the expression of transcripts related to cell-cell adhesion, while RGMa effects on muscle hypertrophy might be due to (i) the activation of the mTOR-Akt independent axis and (ii) the regulation of the expression of transcripts related to atrophy. Finally, RGMa induced the expression of transcripts that encode skeletal muscle structural proteins and members of the signalling pathways associated with GEF and Rho/Rac, common secondary signals of skeletal muscle hypertrophy, and the canonical pathway of the RGMa/Neogenin signalling. Conclusions: These results provide comprehensive knowledge of skeletal muscle transcript changes and pathways in response to RGMa.

show abstract

Large scale serum proteomics identifies proteins associated with performance decline and clinical milestones in Duchenne muscular dystrophy

Ikelaar,

Barnard,

Eng

et al. 2024

Preprint

View full text Add to dashboard Cite

Serum biomarkers are promising minimally invasive outcome measures in clinical studies in Duchenne muscular dystrophy (DMD). However, biomarkers strongly associated with clinical progression and predicting performance decline are lacking. In this study we aimed to identify serum biomarkers associated with clinical performance and able to predict clinical milestones in DMD. Towards this aim we present a retrospective multi-center cohort study including serum samples and clinical data collected in research participants with DMD as part of a natural history study at the University of Florida (UF) and real-world observations at Leiden University Medical Center (LUMC) between 2009-2022. The 7K SomaScan® assay was used to analyse protein levels in in individual serum samples. Serum biomarkers predicted age at loss of ambulation (LoA), age at loss of overhead reach (OHR) and age at loss of hand to mouth function (HTM). Secondary outcomes were the association of biomarkers with age, corticosteroid (CS) usage, and clinical performance based on the North Star Ambulatory Assessment (NSAA), 10 meter run velocity (10mrv), 6 minute walk (6MWT) and Performance of the Upper Limb (PUL2.0). A total of 716 serum samples were collected in 79 participants at UF and 74 at LUMC (mean[SD] age; 10.9[3.2] vs 8.4[3.4]). 244 serum proteins showed an association with CS usage in both cohorts independent of CS type and regimen, including MMP3 and IGLL1. 318 probes (corresponding to 294 proteins) showed significant associations with NSAA, 10mrv, 6MWT and/or PUL2.0 across both cohorts. The expression of 38 probes corresponding to 36 proteins such as RGMA, EHMT2, ART3, ANTXR2 and DLK1 was associated with risk of both lower and upper limb clinical milestones in both the LUMC and UF cohort. In conclusion, multiple biomarkers were associated with CS use, motor function and upper lower and upper limb disease milestones in DMD. These biomarkers were validated across two independent cohorts, increasing their likelihood of translation for use within the broader DMD population.

show abstract

RGMa can induce skeletal muscle cell hyperplasia via association with neogenin signalling pathway

Cited by 5 publications

References 67 publications

Transcriptomic characterization of the molecular mechanisms induced by RGMa during skeletal muscle nuclei accretion and hypertrophy

Transcriptomic characterization of the molecular mechanisms induced by RGMa during skeletal muscle nuclei accretion and hypertrophy

Transcriptomic Characterisation of the Molecular Mechanisms Induced by RGMa During Skeletal Muscle Hyperplasia and Hypertrophy

Large scale serum proteomics identifies proteins associated with performance decline and clinical milestones in Duchenne muscular dystrophy

Contact Info

Product

Resources

About