c-Myc inhibits myoblast differentiation and promotes myoblast proliferation and muscle fibre hypertrophy by regulating the expression of its target genes, miRNAs and lincRNAs

Abstract

The transcription factor c-Myc is an important regulator of cellular proliferation, differentiation and embryogenesis. While c-Myc can inhibit myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that c-Myc does not only inhibits myoblast differentiation but also promotes myoblast proliferation and muscle fibre hypertrophy. By performing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we identified the genome-wide binding profile of c-Myc in skeletal muscle cells. c-Myc achieves its regulatory effects on myoblast proliferation and differentiation by targeting the cell cycle pathway. Additionally, c-Myc can regulate cell cycle genes by controlling miRNA expression of which dozens of miRNAs can also be regulated directly by c-Myc. Among these c-Myc-associated miRNAs (CAMs), the roles played by c-Myc-induced miRNAs in skeletal muscle cells are similar to those played by c-Myc, whereas c-Myc-repressed miRNAs play roles that are opposite to those played by c-Myc. The cell cycle, ERK-MAPK and Akt-mediated pathways are potential target pathways of the CAMs during myoblast differentiation. Interestingly, we identified four CAMs that can directly bind to the c-Myc 3' UTR and inhibit c-Myc expression, suggesting that a negative feedback loop exists between c-Myc and its target miRNAs during myoblast differentiation. c-Myc also potentially regulates many long intergenic noncoding RNAs (lincRNAs). Linc-2949 and linc-1369 are directly regulated by c-Myc, and both lincRNAs are involved in the regulation of myoblast proliferation and differentiation by competing for the binding of muscle differentiation-related miRNAs. Our findings do not only provide a genome-wide overview of the role the c-Myc plays in skeletal muscle cells but also uncover the mechanism of how c-Myc and its target genes regulate myoblast proliferation and differentiation, and muscle fibre hypertrophy.

Benefits of higher resistance‐training volume are related to ribosome biogenesis

“…; Luo et al . ), including greater transition from Type IIX to IIA muscle fibres, greater post‐exercise phosphorylation of S6K1 and ribosomal protein S6, greater post‐exercise expression of c‐Myc and greater rested‐state levels of total RNA and ribosomal RNA. While most of these variables are already assumed to be volume sensitive, such as muscle mass and strength (Krieger, , ; Schoenfeld et al .…”

“…[Colour figure can be viewed at wileyonlinelibrary.com] results from meta-analyses concluding in favour of moderate-compared to low-volume training (Krieger, 2009(Krieger, , 2010Schoenfeld et al 2016). The greater effect of multiple-set training coincided with greater responses in muscle biological traits indicative of hypertrophic response (Andersen & Aagaard, 2000;Terzis et al 2008;Goodman et al 2011;Stec et al 2016;Luo et al 2019), including greater transition from Type IIX to IIA muscle fibres, greater post-exercise phosphorylation of S6K1 and ribosomal protein S6, greater post-exercise expression of c-Myc and greater rested-state levels of total RNA and ribosomal RNA. While most of these variables are already † † † † † † * 300 360 420 480…”

Benefits of higher resistance-training volume depends on ribosome biogenesis

“…This is in agreement with results from meta-analyses concluding in favor of moderate-compared to low-volume training (Krieger, 2009, 2010; Schoenfeld et al ., 2016). The greater effect of multiple-sets training coincided with greater responses in muscle biological traits indicative of hypertrophic response (Andersen & Aagaard, 2000; Goodman et al ., 2011; Terzis et al ., 2008; Luo et al ., 2019; Stec et al ., 2016), including greater transition from Type IIX to IIA muscle fibres, greater post-exercise phosphorylation of mTOR, S6-kinase and ribosomal protein S6, greater post-exercise expression of c-Myc and greater rested-state levels of total RNA and ribosomal RNA. While most of these variables are already assumed to be volume sensitive, such as muscle mass and strength (Krieger, 2009, 2010; Schoenfeld et al ., 2016) and mTOR-signaling (Burd et al ., 2010; Terzis et al ., 2010), this is the first study to suggest that the IIX → IIA fiber switch is also volume sensituive.…”

LncIRS1 controls muscle atrophy via sponging miR‐15 family to activate IGF1‐PI3K/AKT pathway

“…Injections were performed as previously described by Luo with some modifications. Briefly, 1‐day‐old chicks were received three intramuscular doses (single dose injection started at Days 1, 3, and 5) of lentivirus into the breast muscle at dosage of 1 × 10 8 IU/mL.…”