Metabolic reprogramming involving glycolysis in the hibernating brown bear skeletal muscle

Abstract

Background In mammals, the hibernating state is characterized by biochemical adjustments, which include metabolic rate depression and a shift in the primary fuel oxidized from carbohydrates to lipids. A number of studies of hibernating species report an upregulation of the levels and/or activity of lipid oxidizing enzymes in muscles during torpor, with a concomitant downregulation for glycolytic enzymes. However, other studies provide contrasting data about the regulation of fuel utilization in skeletal muscles during hibernation. Bears hibernate with only moderate hypothermia but with a drop in metabolic rate down to ~ 25% of basal metabolism. To gain insights into how fuel metabolism is regulated in hibernating bear skeletal muscles, we examined the vastus lateralis proteome and other changes elicited in brown bears during hibernation. Results We show that bear muscle metabolic reorganization is in line with a suppression of ATP turnover. Regulation of muscle enzyme expression and activity, as well as of circulating metabolite profiles, highlighted a preference for lipid substrates during hibernation, although the data suggested that muscular lipid oxidation levels decreased due to metabolic rate depression. Our data also supported maintenance of muscle glycolysis that could be fuelled from liver gluconeogenesis and mobilization of muscle glycogen stores. During hibernation, our data also suggest that carbohydrate metabolism in bear muscle, as well as protein sparing, could be controlled, in part, by actions of n-3 polyunsaturated fatty acids like docosahexaenoic acid. Conclusions Our work shows that molecular mechanisms in hibernating bear skeletal muscle, which appear consistent with a hypometabolic state, likely contribute to energy and protein savings. Maintenance of glycolysis could help to sustain muscle functionality for situations such as an unexpected exit from hibernation that would require a rapid increase in ATP production for muscle contraction. The molecular data we report here for skeletal muscles of bears hibernating at near normal body temperature represent a signature of muscle preservation despite atrophying conditions. Electronic supplementary material The online version of this article (10.1186/s12983-019-0312-2) contains supplementary material, which is available to authorized users.

Specific shifts in the endocannabinoid system in hibernating brown bears

“…Accordingly, we found that the concentration of total circulating fatty acids was elevated in hibernating bears, a nding in line with previous studies [5,44]. Considering both the amount and relative proportions of circulating lipids, our results are consistent with changes in serum and plasma lipid pro les during hibernation that have been previously published [5,9,10], notably an enrichment in DHA C22:6 n-3 and depletions in ALA C18:3 n-3 and EPA C20:5 n-3, during winter compared to summer. Whether the depletion in the ALA and EPA precursor species could be directly linked to the observed DHA increase remains to be elucidated.…”

“…DHA appears to prevent muscle atrophy in fasting mice, and increases muscle glycogen stores [45]. Strikingly, in parallel to DHA serum enrichment, hibernating bears have more than a 3-fold higher glycogen muscle content compared to summer-active animals [10]. In addition to its anti-in ammatory effects, DHA is also known to exert a positive effect on protein balance by decreasing expression of factors involved in protein breakdown [46] and enhancing protein synthesis, notably by promoting mammalian Target Of Rapamycin (mTOR) activation [47].…”

“…DHA), essentially triggered by DHA dietary intervention studies, could potentially be transposed in the context of hibernation. Indeed, it has already been hypothesized that DHA could be involved in the bear's resistance to muscle atrophy during hibernation [10]. DHA appears to prevent muscle atrophy in fasting mice, and increases muscle glycogen stores [45].…”

“…PDK4 is a major negative regulator of PDH activity, that in turn regulates the whole body oxidative carbohydrate metabolism. In hibernating bear muscle, recent studies have shown that PDK4 is upregulated compared to summer active state [10,61] and expression of PDK4 during hibernation appear thus to be disconnected from direct regulation by CB1. CB1 receptor antagonism also leads to an increased uptake of glucose in muscle via PI3K signaling [60], and glycolysis appears preserved in bear skeletal muscle during hibernation, as suggested by an overall increase in the protein abundance of all glycolytic enzymes [10].…”

“…Brown bears (Ursus arctos) exhibit unique features, as they hibernate at mild hypothermia (32-35°C) and can stay inside their dens for up to 7 months, without drinking, eating, defecating or urinating, and with no arousal episodes [3][4][5][6]. While denning, they reduce their metabolic rate by about 75% [7], and rely primarily on mobilization of fat stores, which is re ected by increased circulating fatty acid concentration and body fat store depletion during winter [8][9][10].…”