Muscle atrophy is associated with many diseases including genetic disorders, sarcopenia, or cachexia syndromes. Myostatin (Mstn), a transforming growth factor‐beta (TGF‐β) member, plays a key role in skeletal muscle homeostasis as a powerful negative regulator. Over the last decade, about 15 clinical trials aimed at inhibiting the Mstn pathway, failed to produce conclusive results. In this context, we investigated whether growth and differentiation factor‐associated serum protein‐1 (GASP‐1) or GASP‐2, two natural inhibitors of Mstn, might represent a potential therapeutic. As we previously reported, mice overexpressing Gasp‐1 (Tg(Gasp‐1)) present an increase of muscle mass but develop metabolic disorders with aging. Here, we showed that overexpression of Gasp‐2 increases the muscular mass without metabolic defects. We also found that Tg(Gasp‐2) mice displayed, like Mstn–/– mice, a switch from slow‐ to fast‐twitch myofibers whereas Tg(Gasp‐1) mice exhibit a reverse switch. Our studies supported the fact that GASP‐2 has less affinity than GASP‐1 for Mstn, leading to a constitutive Mstn upregulation only in Tg(Gasp‐1) mice, responsible for the observed phenotypic differences. Altogether, our findings highlighted a gene expression regulatory network of TGF‐β members and their inhibitors in muscle.

Background: Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor during adulthood. One of the major treatments is the association of surgery and a combination of chemo and radiotherapies. Despite its immediate efficiency, it fails to prevent the cancer recurrence in the irradiated area due to radioresistance mechanisms. MicroRNAs (miRNAs or miR) are small non-coding, single strand RNA molecules encoding to various specific genes and able to regulate their expression and induce the tumor cell survival leading to radioresistance. Small extracellular vesicles (EVs), or exosomes released by tumor cells in tumor microenvironment and blood circulation are able to transport and diffuse miRNAs and affect the microenvironment by spreading the miRNAs, which drive radioresistance. Aims: i)- To identify the variations of miRNAs expression induced by irradiation in human glioblastoma U87-MG cells and their secreted exosomes collected in supernatants. ii)- To analyze the miRNAs variations in EVs-derived from the plasma of patients during radiotherapy, in order to identify a miRNA signature induced by radiotherapy in a liquid biopsy. Materiel and methods: U87-MG cells were cultured on plates and exposed to irradiation. miRNAs analyzes were performed in cells and in EVs isolated from cell supernatants to determine miRNAs expressions both in cells and in secreted exosomes before and after irradiation. Plasma-derived EVs were collected from 4 glioblastoma patients before and after surgery and radiotherapy treatments. Conclusion: The analysis of miRNAs expression profiles in both GBM cells and their derived EVs revealed that miR profile changes after irradiation. However, the number of similar miR between cells or EVs, following cell irradiation, was restricted to 3 miRs alone suggesting that the irradiation-induced changes in the miR profile in the cells and their EVs are not closely linked. In this context, the miR profile in EVs from patients plasma was investigated to establish a potential link with the miRNAs profile observed in EVs from irradiated cells and to assess its relationship with the response to radiotherapy. Three miRs (different from those identified in cells) were common between EVs derived from cells and patients derived-exosomes. These miRs detected in circulating EVs could provide a specific and reliable signature in response to ionizing radiation, which could be useful for monitoring the effectiveness of radiotherapy. Further experiments on a larger patients population with clinical data could also help to define whether this signature might have a prognostic value on the response to radiotherapy.