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

Chazarin Chazarin,Meugnier Meugnier,Lefai Lefai,Evans Evans,Swenson Swenson,Bertile Bertile,Arnemo Arnemo,Blanc Blanc,Ziemianin Ziemianin,Loizon Loizon,Chery Chery,Gauquelin-Koch Gauquelin-Koch,Simon Simon

doi:10.3390/antiox8090334

Abstract

Oxidative stress, which is believed to promote muscle atrophy, has been reported to occur in a few hibernators. However, hibernating bears exhibit efficient energy savings and muscle protein sparing, despite long-term physical inactivity and fasting. We hypothesized that the regulation of the oxidant/antioxidant balance and oxidative stress could favor skeletal muscle maintenance in hibernating brown bears. We showed that increased expressions of cold-inducible proteins CIRBP and RBM3 could favor muscle mass maintenance and alleviate oxidative stress during hibernation. Downregulation of the subunits of the mitochondrial electron transfer chain complexes I, II, and III, and antioxidant enzymes, possibly due to the reduced mitochondrial content, indicated a possible reduction of the production of reactive oxygen species in the hibernating muscle. Concomitantly, the upregulation of cytosolic antioxidant systems, under the control of the transcription factor NRF2, and the maintenance of the GSH/GSSG ratio suggested that bear skeletal muscle is not under a significant oxidative insult during hibernation. Accordingly, lower levels of oxidative damage were recorded in hibernating bear skeletal muscles. These results identify mechanisms by which limited oxidative stress may underlie the resistance to skeletal muscle atrophy in hibernating brown bears. They may constitute therapeutic targets for the treatment of human muscle atrophy.

Highlights

Hibernation is a natural strategy allowing certain mammals to spare energy and survive harsh cold winters with limited food supply [1,2]
Cold-inducible CIRBP, RBM3, and uncoupling protein 3 (UCP3) mRNA levels were 2.8, 4.5, and 1.7-fold higher, respectively, in skeletal muscles of hibernating compared to summer-active bears (Figure 1; N = 8 per season; paired student t-test, p = 0.00007, p = 0.0000005, and p = 0.003, respectively)
The vastus lateralis content in 3-nitrotyrosine was twofold higher in skeletal muscles of hibernating compared to summer-active bears (Figure 4; N = 7 per season; paired student t-test, p = 0.018) and the content in 8-hydroxy-2-deoxy Guanosine (8-OHdG) in DNA extracted from bear skeletal muscle tended to be higher during hibernation but without reaching significance (Figure 4; N = 5 per season; paired student t-test, p = 0.082)

Summary

Introduction

Hibernation is a natural strategy allowing certain mammals to spare energy and survive harsh cold winters with limited food supply [1,2]. ROS are unstable compounds, and when they are present in excess, they may damage biomolecules like nucleic acids, proteins, and lipids These damages can induce a loss of function and cause cell death [10]. Oxidative stress is triggered in relation with a number of conditions, including for example immune cell activation, inflammation, ischemia, infection, cancer, mental stress, food deprivation, and aging [10,12,13,14]. Oxidative stress has been reported to be induced in various disease states [15,16], and by exercise [17], microgravity conditions [18], fasting [19], and muscle disuse [20] In these latter examples, oxidative stress has been directly connected to the promotion of muscle proteolysis and inhibition of protein synthesis, thereby contributing to muscle atrophy [20]

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