Genetic reprogramming involving a shift from TGF- β to BMP signaling for muscle mass maintenance in hibernating brown bear

National audience

English. Muscle atrophy arises from a multiplicity of situations (disuse, cancer, myopathies, aging etc), caused by an imbalance between protein synthesis and breakdown. The E3/E2s enzymes play a predominant role in muscle proteolytic machinery by targeting contractile proteins for degradation ; hence some of are refered as atrogenes (atrophy-related genes). Even though knowledge about the underlying mechanisms keep expand from induced-atrophy models, there is still no therapeutic or preventive treatment to date. In this context, we propose a non-common approach using a model of muscle atrophy resistance, the hibernating brown bear. Remarkably, this mammalian does not display muscle wasting during hibernation, being evolutionarily adapted to the two major atrophic inducers, immobilization and fasting. Consequently, to discern the adaptive mechanisms involved in muscle atrophy resistance, we explore brown bear muscle transcriptomic in summer active versus winter hibernating period. Expression of the usual atrogenes did not vary between the two seasons. Interestingly, we noted changes in expression of some E3s identified as participating in TGF-β super family inhibition, a cellular pathway divided in two canonical signaling: TGF-β signaling known to be overregulated in muscle atrophy and BMP signaling involved in muscle mass maintenance. First, TGF-β signaling appears to be curbed with i) a downregulation of the ligands TGF-β1/3 expression, and ii) an overexpression of the E3s NEDD4L, TRIM33 restraining the signal transduction. On the other hand, BMP signaling seems to be reinforced with i) an upregulation of SMAD1, BMP14, HOXC8 and ii) a down-regulation of the BMP signaling negative regulator, STUB1. Collectively, our data suggest a shift from TGF-β to BMP signaling for muscle mass maintenance in hibernating brown bear and highlight the BMP pathway as a potential therapeutic target to prevent muscle atrophy.