The B-STRONG project aims to provide new weapons in the fight against human muscle atrophy, a major public health problem. Indeed, the loss of muscle is associated with a reduction in the autonomy of patients (sedentary, malnourished, elderly, or suffering from cachexia) and with the development of metabolic inflexibility and insulin resistance. Up to now, no therapeutic or preventive strategy has proven to be fully effective to prevent or cure people suffering from muscle wasting. However, our past studies in the brown bear, a model of natural resistance to muscle atrophy during hibernation, pave the way to new research strategies. Through a bio-inspired approach, B-STRONG proposes to focus on the therapeutic potential of a modulation of the BMP/TGF-beta balance. Although therapies targeting inhibition of the deleterious effects of TGF-beta are numerous, the BMP signalling pathway, inseparable from that of TGF-beta, has been rarely targeted to date. However, our latest results show that maintaining BMP signalling and simulatenous inhibition of TGF-beta signalling are essential features of muscle preservation in hibernating brown bears, as they face atrophic conditions (prolonged physical inactivity and total fasting). We had also previously shown that hibernating bear serum has strong anti-proteolytic activity when applied to human muscle cells in vitro. Therefore, B-STRONG will identify the bear’s serum compounds that are responsible for protecting muscle mass via modulation of the BMP/TGF- beta balance, and it will decipher the signalling pathways involved. First, the molecular signature of the effects of bear serum on human primary myotubes will be established. Genetic and pharmacological strategies will be used to modulate key players in these pathways. In parallel, bear serum will be fractionated and fractions will be screened for their ability to trigger changes in the BMP/TGF-beta balance in cultured human cells. Active bear serum fractions/compounds will thus be identified, and then assessed for their potential to prevent or reverse an induced atrophy using in vitro muscle cell models. The ability of the most promising compound/target to prevent/reverse muscle loss will be explored in vivo in mouse models of induced muscle atrophy. Overall, the project will produce scientific knowledge regarding the regulation of muscle mass and identify active bear serum fractions and/or compounds capable of controlling muscle plasticity. All these aspects will be of major interest to the scientific and medical communities who hope for new levers to fight human muscle atrophy. To achieve these objectives, B-STRONG relies on 2 partners with complementary and internationally recognized expertise in their respective fields, analytical chemistry applied to animal adaptations to the environment and the pathophysiology and molecular mechanisms of muscle atrophy.