MicroRNAs facilitate skeletal muscle maintenance and metabolic suppression in hibernating brown bears

Luu, Bryan E.; Lefai, Étienne; Giroud, Sylvain; Swenson, Jon E.; Chazarin, Blandine; Gauquelin‐Koch, Guillemette; Arnemo, Jon M.; Evans, Alina L.; Bertile, Fabrice; Storey, Kenneth B.

doi:10.1002/jcp.29294

Cited by 21 publications

(21 citation statements)

References 62 publications

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“…MicroRNAs (miRNAs) are a category of highly conserved small noncoding RNAs that are able to mediate the fate of mRNA transcripts responding to all kinds of signaling pathways in cells. 7 Some researches show the link of miRNAs with AS. For example, a study indicates that up-regulated miR-377 partly relieves the progress of AS.…”

Section: Introductionmentioning

confidence: 99%

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA‐139‐5p methylation and signal transducer and activator of transcription 1 expression

et al. 2020

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Atherosclerosis (AS) is the main cause of coronary heart disease, in which enhancer of zeste homolog 2 (EZH2) has been implied to participate in this process. Thus, this work proposed to explore the effect of EZH2 on AS from microRNA‐139‐5p (miR‐139‐5p)/signal transducer and activator of transcription 1 (STAT1) axis. EZH2, miR‐139‐5p, and STAT1 expression in arterial tissues of AS patients were detected. Human arterial smooth muscle cells (HASMCs) induced with oxidized low‐density lipoprotein (ox‐LDL) and the mice fed with high fat diet were treated with silenced EZH2 or upregulated miR‐139‐5p to explore their roles in proliferation and apoptosis of HASMCs, together with inflammation response and oxidative stress of mice. Chromatin immunoprecipitation experiment was applied to verify the regulatory effect of EZH2 on miR‐139‐5p through methylation of H3K27me3. The targeting relationship between miR‐139‐5p and STAT1 was verified by online website and luciferase activity assay. Reduced miR‐139‐5p and overexpressed EHZ2 and STAT1 were found in AS. Silenced EZH2 or elevated miR‐139‐5p decreased the production of cholesterol and inhibited inflammation reaction in serum of mice with AS. Silenced EZH2 or elevated miR‐139‐5p facilitated proliferation and restrained apoptosis of ox‐LDL‐treated HASMCs, and restrained oxidative stress and cell apoptosis in arterial tissues of AS mice. EZH2 regulated miR‐139‐5p through H3K27me3, and miR‐139‐5p targeted STAT1. miR‐139‐5p silencing antagonized the effects of EZH2 down‐regulation on AS. This study manifests that down‐regulated EZH2 or elevated miR‐139‐5p inhibits ox‐LDL‐induced HASMCs apoptosis, plaque formation, and inflammatory response in AS mice, which may be related to down‐regulated STAT1.

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Section: Introductionmentioning

confidence: 99%

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA‐139‐5p methylation and signal transducer and activator of transcription 1 expression

et al. 2020

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“…Finally, higher levels of metabolic microRNAs during hibernation have been reported to be responsible for metabolic suppression and for the activation of myogenic pathways, decreasing atrophic signaling (Luu et al, 2020). Taken together, these findings suggest that brown bears are able to maintain both muscle mass and function by reducing catabolic processes and maintaining a certain level of mechanical activity.…”

Section: Skeletal Response To Hibernation Bone Turnover and Changementioning

confidence: 86%

Denning in brown bears

González-Bernardo

Russo

Valderrábano

et al. 2020

Ecology and Evolution

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Hibernation represents an adaptation for coping with unfavorable environmental conditions. For brown bears Ursus arctos, hibernation is a critical period as pronounced temporal reductions in several physiological functions occur. Here, we review the three main aspects of brown bear denning: (1) den chronology, (2) den characteristics, and (3) hibernation physiology in order to identify (a) proximate and ultimate factors of hibernation as well as (b) research gaps and conservation priorities. Den chronology, which varies by sex and reproductive status, depends on environmental factors, such as snow, temperature, food availability, and den altitude. Significant variation in hibernation across latitudes occurs for both den entry and exit. The choice of a den and its surroundings may affect individual fitness, for example, loss of offspring and excessive energy consumption. Den selection is the result of broad‐ and fine‐scale habitat selection, mainly linked to den insulation, remoteness, and availability of food in the surroundings of the den location. Hibernation is a metabolic challenge for the brown bears, in which a series of physiological adaptations in tissues and organs enable survival under nutritional deprivation, maintain high levels of lipids, preserve muscle, and bone and prevent cardiovascular pathologies such as atherosclerosis. It is important to understand: (a) proximate and ultimate factors in denning behavior and the difference between actual drivers of hibernation (i.e., factors to which bears directly respond) and their correlates; (b) how changes in climatic factors might affect the ability of bears to face global climate change and the human‐mediated changes in food availability; (c) hyperphagia (period in which brown bears accumulate fat reserves), predenning and denning periods, including for those populations in which bears do not hibernate every year; and (d) how to approach the study of bear denning merging insights from different perspectives, that is, physiology, ecology, and behavior.

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“…However, several hypotheses can be raised; our recent analysis of muscle proteome in the hibernating brown bear revealed the maintenance of glycolysis and a turning down of ATP turnover [32]. In addition, we reported (i) a myogenic microRNA signature prone to promoting muscle regeneration and suppressing ubiquitin ligase expression in bear muscle during winter [33], as well as (ii) limited levels of oxidative stress [34]. To unravel the molecular basis of muscle maintenance at the mRNA level, the bear muscle transcriptome has already been explored using cDNA microarrays [35] or RNA sequencing [36,37].…”

Section: Introductionmentioning

confidence: 87%

Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear

Cussonneau

Boyer

Brun

et al. 2021

Cells

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Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of induced atrophy, the unloaded mouse. Using RNA sequencing, we identified 4415 differentially expressed genes, including 1746 up- and 2369 down-regulated genes, in bear muscles between the active versus hibernating period. We focused on the Transforming Growth Factor (TGF)-β and the Bone Morphogenetic Protein (BMP) pathways, respectively, involved in muscle mass loss and maintenance. TGF-β- and BMP-related genes were overall down- and up-regulated in the non-atrophied muscles of the hibernating bear, respectively, and the opposite occurred for the atrophied muscles of the unloaded mouse. This was further substantiated at the protein level. Our data suggest TGF-β/BMP balance is crucial for muscle mass maintenance during long-term physical inactivity in the hibernating bear. Thus, concurrent activation of the BMP pathway may potentiate TGF-β inhibiting therapies already targeted to prevent muscle atrophy.

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MicroRNAs facilitate skeletal muscle maintenance and metabolic suppression in hibernating brown bears

Cited by 21 publications

References 62 publications

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA‐139‐5p methylation and signal transducer and activator of transcription 1 expression

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA‐139‐5p methylation and signal transducer and activator of transcription 1 expression

Denning in brown bears

Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear

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