Muscle loss (atrophy) is observed in several physio-pathological situations and has very harmful consequences for the patients. However, despite a thorough understanding of muscle atrophy mechanisms using rodent and human models, no effective treatment is yet available. We use a bioinspired approach from the brown bear, which is naturally resistant to muscle atrophy during winter hibernation. We previously reported that this phenotype was associated with the maintenance or activation of the BMP (Bone Morphogenetic Protein) pathway (1), which positively controls muscle mass. We have also shown that winter bear serum (WBS) displays translational effects on human myotubes by inducing hypertrophy (2). Here, we aimed at further investigating the effect of WBS on human myotubes using large-scale transcriptomic analysis (mRNA sequencing) complemented using Western-blots. We identified 24,826 genes, of which 352 were differentially expressed between human myotubes cultivated for 48h with 5% of WBS or summer bear serum (SBS). Functional annotation analysis using the Gene Ontology resource revealed significant enrichment of biological processes related to (i) muscle function, (ii) extracellular matrix remodeling and (iii) negative regulation of BMP signaling. More precisely, we observed that several BMP signaling endogenous inhibitors were down-regulated at the mRNA and protein levels. Overall, these data show that hibernating bear serum induces transcriptomic reprogramming of BMP signaling regulation in human myotubes. Furthermore, the down-regulation of BMP inhibitors suggests a reduction in the repressive processes of the BMP pathway. Further studies will investigate how this reprogramming might influence BMP signaling and/or muscle mass maintenance under catabolic conditions. (1) Cussonneau et al. Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear. Cells. 2021. 10(8):1873. doi: 10.3390/cells10081873. (2) Chanon et al. Proteolysis inhibition by hibernating bear serum leads to increased protein content in human muscle cells. Sci Rep. 2018. 8(1):5525. doi: 10.1038/s41598-018-23891-5.