ORIGINAL ARTICLEAntiproteolytic effects of plasma from hibernating bears: A new approach for muscle wasting therapy?☆
Introduction
The precise mechanism by which intracellular proteins are degraded is largely unknown, although it is accepted that proteolysis may occur inside and outside the lysosomes. The ATP-ubiquitin-dependent proteolytic system has been shown to be involved in the alterations of protein metabolism related to several pathophysiological conditions such as cancer, chronic infection and chronic heart failure.1, 2 During the pathological conditions commented on, muscle wasting leads to cachexia, a syndrome characterized by weight loss and profound metabolic abnormalities. Unfortunately therapeutic approaches to stop muscle wasting have not been very satisfactory, partly because of the toxicity of inhibitors of the ubiquitin-dependent proteolytic system. In addition, this proteolytic system is involved in many biological processes, such as cell proliferation and intracellular signaling.3 Therefore, a non-muscle specific inhibition would result in dramatic toxic effects for the organism. Interestingly, muscle wasting is also observed in non-pathological conditions, such as immobilization or microgravity, where an important muscle atrophy develops. In these conditions, an activation of the ubiquitin-dependent proteolytic system has also been described.4
Hibernating animals, such as bears, stay inside their winter dens for periods of at least 4 months. During this “sleeping” period they do not eat or have any physiological activity. In spite of this starvation and immobilization period, they do not develop muscle atrophy (their weight loss only includes adipose tissue mobilization), unlike humans, who would be weakened by 90% strength loss over the same period.5
In view of this observation, we hypothesized that a type of inhibitory activity on skeletal muscle proteolysis must be induced during hibernation. Bearing this in mind, we decided to test if hibernating bear plasma has any antiproteolytic effect on incubated rat skeletal muscle.
Section snippets
Bear plasma
Bear plasma was obtained from Ursus arctos. Sample collection was carried out in their natural habitat (Pirinees, Artíes, Vall d’Aran) using anesthesia.
Animals
Male Wistar rats (Interfauna, Barcelona, Spain) weighing about 60 g were used. The animals were maintained on a regular light–dark cycle (light on from 08:00 a.m. to 08:00 p.m.) at an ambient temperature of 22±2 °C and had free access to food and water. The diet (B.K. Universal, Sant Vicents dels Horts, Barcelona, Spain) consisted of 45.5–48.5%
Results
The results presented in Table 1 clearly show that the presence of hibernating plasma resulted in a 40% decrease of the proteolytic rate, as compared with the muscles incubated in the presence of non-hibernating bear plasma. It is therefore clear from these results that a material present in the plasma during hibernation is able to block total proteolysis. Bearing all this in mind, we decided to assess the expression of genes involved in protein breakdown. As observed in Table 2, both cathepsin
Discussion
Hibernating animals are subject to both extreme starvation and immobilization. In non-hibernating mammals, such as humans, these two conditions led to a massive and dangerous muscle wasting associated with cachexia. However, during hibernation, the animals do not experience muscle wasting,5 therefore indicating that neither starvation nor immobilization can trigger the proteolysis induction that takes place in skeletal muscle during wasting. The decrease of net proteolytic rate in incubated rat
Acknowledgments
This work was supported by grants from the Instituto de Salud Carlos III (03/0100) of the Ministerio de Sanidad y Consumo, from the Dirección General de Investigación Científica y Técnica (SAF4744-2005) of the Ministerio de Educación y Ciencia, from the Generalitat de Catalunya (SGR/00108), from Ministerio de Ciencia y Tecnologia (VIN03/021), and by grant SAF-2003-04223 from the Ministerio de Ciencia y Tecnología (MCyT). Special thanks to Jesús Fernández, (Zoologic de Barcelona) and Santiago
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Cited by (26)
Serum plays an important role in reprogramming the seasonal transcriptional profile of brown bear adipocytes
2022, iScienceCitation Excerpt :The current findings identifying eight serum proteins that are uniquely expressed provide a starting point in the elucidation of their unique actions. Together with this information, we can begin to explore the applications of proteins identified in bears to human pathologies, including muscle wasting and osteoporosis (Donahue et al., 2006; Fuster et al., 2007; Harlow et al., 2001; Hershey et al., 2008; Lin et al., 2012; Lohuis et al., 2007), kidney disease (Stenvinkel et al., 2013), and metabolic syndrome (Berg von Linde et al., 2015; Martin, 2008; Rigano et al., 2017; Wu et al., 2013). It is possible that metabolites and/or additional serum proteins that were not detected in this study could play an important role in the regulation of hibernation phenotypes.
Biochemical foundations of health and energy conservation in hibernating free-ranging subadult brown bear ursus arctos
2016, Journal of Biological ChemistryCitation Excerpt :Bear and human A2M are 81% identical in sequence and do cross-react, because of their large 180-kDa subunit sizes, which increase the probability of conserved immunogenic epitopes. Intriguingly, Fuster et al. (30) reported a 40% decrease in protein degradation of isolated rat skeletal muscle incubated with plasma of hibernating brown bear versus controls without bear plasma. We propose the most likely inhibitor candidate is A2M.
Hibernating bears (Ursidae): Metabolic magicians of definite interest for the nephrologist
2013, Kidney InternationalCitation Excerpt :Two novel observations have helped to further elucidate this fascinating metabolic adaption in bears. Fuster et al.39 demonstrated that hibernating bears produce a powerful proteolytic inhibitor that blocks muscle wasting associated with immobilization. If this factor could be identified, it could serve as a treatment strategy for conditions in which protein energy wasting is a common feature.
Cachexia and aging: An update based of the Fourth International Cachexia Meeting
2009, Journal of Nutrition, Health and Aging
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Conference presentation: The work was presented by Prof. Josep M. Argilés in the 11th world congress on advances in oncology, Hersonissos, Creta, 2006/10/12.
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These authors contributed equally to this work.