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Limited Oxidative Stress Favors Resistance to Skeletal Muscle Atrophy in Hibernating Brown Bears (Ursus Arctos)

Fabrice Bertile

Muscle atrophy is an inevitable part of ageing, disuse, starvation, or microgravity. Its molecular bases are well deciphered thanks to studies in mice under weightlessness or using the bed rest model in humans. However, a fully effective therapy is still lacking. Screening biodiversity holds potential to find new ways of potential medical interest. Indeed, muscles are fairly well preserved in hibernating animals despite long inactive and fasting periods. To unravel the underlying mechanisms, we compared brown bear (Ursus arctos) tissues collected during the summer-active season versus hibernation using a combination of omics techniques and biochemistry methods. We identified several mechanisms likely involved in brown bear resistance to muscle atrophy during hibernation, and possibly transferable to humans. Examination of the general and regional oxidant/antioxidant balance and oxidative damages during summer versus winter, notably highlited greater plasma-antioxidant capacity, and both white adipose tissue and skeletal muscles appeared protected from oxidative stress during hibernation. Because, oxidative stress promotes proteolysis and inhibits protein synthesis, its limitation during hibernation likely contributes to muscle protein sparing. Additionally, we highlighted inhibition of TGF signalling, maintenance of BMP signalling, and elicitation of a myogenic microRNA response via MEF2A. Despite a preference for lipid substrates during hibernation, muscle glycolysis was maintained and elevated levels of muscle glycogen stores were measured. Carbohydrate metabolism and protein sparing in hibernating bears could be controlled by the higher concentrations of plasma docosahexaenoic acid during winter. We finally observed that the serum from hibernating bears strongly inhibits proteasomal and lysosomal proteolysis in human muscle cells in vitro. The natural resistance of hibernating bears to muscle atrophy appears controlled through a coordinated regulatory program. Transfer of bear protein sparing strategies to humans, notably after identification of serum antiproteolytic factors, is expected to help better fight muscle wasting in aged or sedentary people, and in astronauts.


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