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

Abstract

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.

Division-Independent Differentiation of Muscle Stem Cells During a Growth Stimulus

“…MuSCs in cluster 6 expressed high levels of genes encoding ribosomal proteins ( Rps2 and Rpl3 ) and genes expressed during the pre-fusion phase ( Myof ). 50 Furthermore, a subset of MuSCs in clusters 8 and 9 displayed high levels of myogenic genes ( Myog , Fig. 1D ; Itga7 , Supplementary Fig.…”

New Genomic Insights into the Conformation of Lipizzan Horses

“…In humans, it is common that adults affected by Type 2 Diabetes, lose skeletal muscle mass 29 . It has also been shown that certain Pou2f1 isoforms were either heavily up-or downregulated by Repulsive guidance molecule a (RGMa), important in skeletal cell differentiation, cell fusion and hypertrophy 30 , which could contribute to explain the gradient between heavy-type and light-type horses. In livestock, MAGI1 was previously associated with average daily gain and Kleiber ratio (average daily gain / end weight 0.75 ) in 6-to 9month-old sheep 31 .…”

New genomic insights into the conformation of Lipizzan horses

“…In the Brazilian Nellore cattle, a QTL containing the POU2F1 gene explained 41% of genetic variance in conformation and 29% in muscling scores 33 and was also identified as one of the major transcription factors regulating growth and fatty deposits in Iberian × Landrace pigs 34 . In humans, certain Pou2f1 isoforms were either heavily up- or downregulated by repulsive guidance molecule a (RGMa), important in skeletal cell differentiation, cell fusion and hypertrophy 35 . POU2F1 variants were also associated with human Type 2 Diabetes Mellitus 36 , 37 , and it is common that adults affected by Type 2 Diabetes lose skeletal muscle mass 38 .…”