Hibernating brown bear serum modulates the balance of TGF-β and BMP pathways in human muscle cells

Muscle atrophy is observed in several pathophysiological situations, including physical inactivity, leading to negative health consequences, without any effective treatment currently available. Conversely, brown bears resist muscle atrophy during hibernation, despite prolonged physical inactivity and fasting. We previously reported that hibernating brown bear serum increases protein content in human myotubes and inhibits proteolysis. To go further, we deciphered here the transcriptional effects of brown bear serum in human myotubes using large-scale transcriptomics. After 48hours, the winter-hibernating bear serum (WBS) induced a specific transcriptomic program, affecting mostly biological pathways related to muscle growth and BMP signalling, compared to the summer-active bear (SBS) serum. WBS predominantly reduced, at mRNA and protein levels, activators and inhibitors of BMP signalling, which is associated with muscle mass maintenance. Moreover, BMP activity was more responsive to a stimulation by BMP7 at supra-physiological concentrations in human myotubes cultured in WBS versus SBS conditions. Meanwhile, WBS also up-regulated expression of genes encoding repressors of the pro-atrophic TGF-β pathway, decreased phosphorylated SMAD3 nuclear protein levels, and down-regulated TGF-β target genes. Furthermore, WBS treatment resulted in reduced TGF-β signalling responsiveness in human myotubes stimulated with TGF-β3 at physiological concentrations. Overall, even though WBS induced larger transcriptomic changes in the BMP compared to TGF-β pathway, the functional consequences were more pronounced for the TGF-β pathway with a marked inhibition. This study suggests that bioactive compounds in WBS may protect human muscle cells during catabolic situations, by regulating the TGF-β/BMP balance. These findings open new perspectives for therapies targeting muscle atrophy.