Muscle atrophy arises from a multiplicity of physiological or pathological situations (e.g. diabetes, cancers, aging, physical inactivity…) and its consequences are very detrimental at whole-body level. Even though knowledge of the underlying mechanisms keeps growing, there is still no proven treatment to date. To address this major clinical challenge, we selected here an innovative approach that compares muscle adaptations between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of disuse-induced atrophy in mouse. Remarkably, the bear has the unique ability to withstand muscle loss during hibernation, being able to cope with main triggers of atrophy, physical inactivity and prolonged fasting. Using transcriptomic analysis by RNA sequencing, we identified 2693 differentially expressed genes between the active versus hibernating period in bear muscle. We focused on TGF-β and BMP signaling pathways that are respectively involved in muscle mass loss and maintenance. During hibernation, gene expression of the TGF-β and BMP pathways components was overall downregulated and upregulated, respectively. On the contrary, an increased expression of TGF-β signaling genes and a decreased expression of BMP signaling genes was observed in mice muscles during unloading. We have further substantiated this opposite regulation between atrophied muscles of the unloaded mouse and non-atrophied muscles of the hibernating bear at the protein level. Altogether, our data identified a balance between TGF-β and BMP signaling pathways as crucial for muscle mass maintenance during long-term physical inactivity. In addition to the TGF-β pathway, already targeted in a wide range of therapies, the BMP pathway therefore appears to be an additional potential therapeutic target to prevent muscle atrophy.