TY - JOUR
T1 - Circulating insulin-like growth factor system adaptations in hibernating brown bears indicate increased tissue IGF availability
AU - Frøbert, Anne Mette
AU - Brohus, Malene
AU - Roesen, Tinna S.
AU - Kindberg, Jonas
AU - Fröbert, Ole
AU - Conover, Cheryl A.
AU - Overgaard, Michael T.
N1 - Funding Information:
This work was supported by grant R126-2012-12408 (to O. Fro€bert and M. T. Overgaard) and PhD grant R286-2018-367 (to A. M. Frøbert) from The Lundbeck Foundation.
Publisher Copyright:
© 2022 the American Physiological Society.
PY - 2022/9
Y1 - 2022/9
N2 - 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 (n = 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 (n = 6). Analysis of available grizzly bear RNA sequencing data revealed unaltered liver mRNA IGF-1, IGFBP- 2, and IGFBP-3 levels, whereas ALS levels were significantly reduced during hibernation (n = 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 IGF-2 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.
AB - 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 (n = 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 (n = 6). Analysis of available grizzly bear RNA sequencing data revealed unaltered liver mRNA IGF-1, IGFBP- 2, and IGFBP-3 levels, whereas ALS levels were significantly reduced during hibernation (n = 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 IGF-2 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.
KW - acid labile subunit (ALS)
KW - hibernation
KW - IGF-binding protein (IGFBP)
KW - insulin-like growth factor (IGF)
KW - Ursus arctos
KW - Insulin-Like Growth Factor Binding Proteins/metabolism
KW - Insulin-Like Growth Factor Binding Protein 3/metabolism
KW - Animals
KW - Insulin-Like Growth Factor Binding Protein 2/metabolism
KW - Ursidae/metabolism
KW - Insulin-Like Growth Factor II/metabolism
KW - Insulin-Like Growth Factor I/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85138126972&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00429.2021
DO - 10.1152/ajpendo.00429.2021
M3 - Journal article
C2 - 35830688
AN - SCOPUS:85138126972
SN - 0193-1849
VL - 323
SP - E307-E318
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 3
ER -