Department of Chemistry and Bioscience, Faculty of Engineering and Science, Aalborg University, Aalborg, Denmark.
Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
Am J Physiol Endocrinol Metab. 2022 Sep 1;323(3):E307-E318. doi: 10.1152/ajpendo.00429.2021. Epub 2022 Jul 13.
Brown bears conserve muscle and bone mass during 6 mo of inactive hibernation. The molecular mechanisms underlying hibernation physiology may have translational relevance for human therapeutics. We hypothesize that protective mechanisms involve increased tissue availability of insulin-like growth factors (IGFs). In subadult Scandinavian brown bears, we observed that mean plasma IGF-1 and IGF-2 levels during hibernation were reduced to 36 ± 10% and 56 ± 15%, respectively, compared with the active state ( = 12). Western ligand blotting identified IGF-binding protein (IGFBP)-3 as the major IGFBP in the active state, whereas IGFBP-2 was codominant during hibernation. Acid labile subunit (ALS) levels in hibernation were reduced to 41±16% compared with the active state ( = 6). Analysis of available grizzly bear RNA sequencing data revealed unaltered liver mRNA , , and levels, whereas levels were significantly reduced during hibernation ( = 6). Reduced ALS synthesis and circulating levels during hibernation should prompt a shift from ternary IGF/IGFBP/ALS to smaller binary IGF/IGFBP complexes, thereby increasing IGF tissue availability. Indeed, size-exclusion chromatography of bear plasma demonstrated a shift to lower molecular weight IGF-containing complexes in the hibernating versus the active state. Furthermore, we note that the major mRNA isoform expressed in livers in both Scandinavian brown bears and grizzly bears was an alternative splice variant in which Ser29 is replaced with a tetrapeptide possessing a positively charged Arg residue. Homology modeling of the bear IGF-2/IGFBP-2 complex showed the tetrapeptide in proximity to the heparin-binding domain involved in bone-specific targeting of this complex. In conclusion, this study provides data which suggest that increased IGF tissue availability combined with tissue-specific targeting contribute to tissue preservation in hibernating bears. Brown bears shift from circulating ternary IGF/IGFBP/ALS complexes in the active state to binary IGF/IGFBP complexes during hibernation, indicating increased tissue IGF-bioactivity. Furthermore, brown bears use a splice variant of IGF-2, suggesting increased bone-specific targeting of IGF anabolic signaling.
棕熊在 6 个月的休眠期内保持肌肉和骨量。冬眠生理学的分子机制可能对人类治疗具有转化相关性。我们假设，保护机制包括增加胰岛素样生长因子（IGF）的组织可用性。在未成年的斯堪的纳维亚棕熊中，我们观察到冬眠期间的平均血浆 IGF-1 和 IGF-2 水平分别降低到 36±10%和 56±15%，与活跃状态相比（ = 12）。Western 配体印迹鉴定 IGF 结合蛋白（IGFBP）-3 为活跃状态下的主要 IGFBP，而 IGFBP-2 在冬眠期间占主导地位。冬眠期间酸不稳定亚基（ALS）水平降低到 41±16%，与活跃状态相比（ = 6）。对可用的灰熊 RNA 测序数据的分析显示，肝脏 mRNA 、 、 和 水平不变，而在冬眠期间 水平显著降低（ = 6）。冬眠期间 ALS 合成和循环水平的降低应促使从三元 IGF/IGFBP/ALS 转变为较小的二元 IGF/IGFBP 复合物，从而增加 IGF 的组织可用性。事实上，熊血浆的排阻色谱法显示，在休眠状态下，IGF 含量较低的复合物向较低分子量的 IGF 含量复合物发生转变。此外，我们注意到，在斯堪的纳维亚棕熊和灰熊的肝脏中表达的主要 IGF-2 信使 RNA 同工型是一种替代剪接变体，其中 Ser29 被一个带有正电荷 Arg 残基的四肽取代。熊 IGF-2/IGFBP-2 复合物的同源建模显示，该四肽与肝素结合域接近，该结合域参与该复合物的骨特异性靶向。总之，这项研究提供的数据表明，增加的 IGF 组织可用性与组织特异性靶向相结合，有助于冬眠熊的组织保存。棕熊在休眠期间从活跃状态下的循环三元 IGF/IGFBP/ALS 复合物转变为二元 IGF/IGFBP 复合物，表明组织 IGF 生物活性增加。此外，棕熊使用 IGF-2 的剪接变体，表明 IGF 合成代谢信号的骨特异性靶向增加。
