bims-cesemi 2024-12-15 papers

Issue of 2024–12–15
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor

Nat Aging. 2024 Dec 10.

IL-23R is a senescence-linked circulating and tissue biomarker of aging.

Chase M Carver, Sonia L Rodriguez, Elizabeth J Atkinson, Andrew J Dosch, Niels C Asmussen, Paul T Gomez, Ethan A Leitschuh, Jair M Espindola-Netto, Karthik B Jeganathan, Madison G Whaley, Theodore M Kamenecka, Darren J Baker, Andrew J Haak, Nathan K LeBrasseur, Marissa J Schafer.

Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.

DOI: https://doi.org/10.1038/s43587-024-00752-7

Cell Calcium. 2024 Nov 29. pii: S0143-4160(24)00138-6. [Epub ahead of print]125 102980

STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis.

Maria Livia Sassano, Robbe Van Gorp, Geert Bultynck, Patrizia Agostinis.

The endoplasmic reticulum (ER) controls intracellular Ca2+ dynamics. Depletion of ER Ca2+ stores results in short-term activation of store-operated Ca2+ entry (SOCE) via STIM1/Orai1 at ER-plasma membrane (ER-PM) contact sites (MCSs) and the long-term activation of the unfolded protein response (UPR), securing ER proteostasis. Recent work by Carreras-Sureda and colleagues describes a bidirectional control between IRE1 and STIM1 within the ER lumen that regulates ER-PM contact assembly and SOCE to sustain T-cell activation and myoblast differentiation.

Keywords: IP3 receptors; IRE1; STIM1; Store-operated calcium entry; Unfolded protein response

DOI: https://doi.org/10.1016/j.ceca.2024.102980

bioRxiv. 2024 Nov 26. pii: 2024.11.25.625228. [Epub ahead of print]

Mechanism of MCUB-dependent inhibition of mitochondrial calcium uptake.

Neeraj K Rai, Anthony M Balynas, Melissa Js MacEwen, Ashley R Bratt, Yasemin Sancak, Dipayan Chaudhuri.

Mitochondrial Ca 2+ levels are regulated to balance stimulating respiration against the harm of Ca 2+ overload. Contributing to this balance, the main channel transporting Ca 2+ into the matrix, the mitochondrial Ca 2+ uniporter, can incorporate a dominant-negative subunit (MCUB). MCUB is homologous to the pore-forming subunit MCU, but when present in the pore-lining tetramer, inhibits Ca 2+ transport. Here, using cell lines deleted of both MCU and MCUB, we identify three factors that contribute to MCUB-dependent inhibition. First, MCUB protein requires MCU to express. The effect is mediated via the N-terminal domain (NTD) of MCUB. Replacement of the MCUB NTD with the MCU NTD recovers autonomous expression but fails to rescue Ca 2+ uptake. Surprisingly, mutations to MCUB that affect interactions with accessory subunits or the conduction pore all failed to rescue Ca 2+ uptake, suggesting the mechanism of inhibition may involve global rearrangements. Second, using concatemeric tetramers with varying MCU:MCUB ratios, we find that MCUB incorporation does not abolish conduction, but rather inhibits Ca 2+ influx proportional to the amount of MCUB present in the channel. Reducing rather than abolishing Ca 2+ transport is consistent with MCUB retaining the highly-conserved selectivity filter DIME sequence. Finally, we apply live-cell Förster resonance energy transfer to establish that the endogenous stoichiometry is 2:2 MCU:MCUB. Taken together, our results suggest MCUB preferentially incorporates into nascent uniporters, and the amount of MCUB protein present linearly correlates with the degree of inhibition of Ca 2+ transport, creating a precise, tunable mechanism for cells to regulate mitochondrial Ca 2+ uptake.

DOI: https://doi.org/10.1101/2024.11.25.625228

Aging (Albany NY). 2024 Dec 12. null

Arginase-II gene deficiency reduces skeletal muscle aging in mice.

Matteo Caretti, Duilio Michele Potenza, Guillaume Ajalbert, Urs Albrecht, Xiu-Fen Ming, Andrea Brenna, Zhihong Yang.

Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (wt) mice and mice deficient in arg-ii (arg-ii-/-) of both sexes are investigated. We demonstrate a decreased physical performance of old wt mice, which is partially prevented in arg-ii-/- animals, particularly in males. The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice. Finally, we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.

Keywords: aging; arginase-II; cellular senescence; fibrosis; physical activity; skeletal muscle

DOI: https://doi.org/10.18632/aging.206173

Nature. 2024 Dec 13.

Fasting can reduce weight - but also hair growth.

Max Kozlov.

Keywords: Cell biology; Metabolism; Regeneration; Stem cells

DOI: https://doi.org/10.1038/d41586-024-04084-9

J Appl Physiol (1985). 2024 Dec 12.

An IL-6 promoter variant (-174 G/C) augments IL-6 production and alters skeletal muscle transcription in response to exercise in mice.

L E Watson, C L MacRae, P Kallingappa, Y Cao, X Li, C P Hedges, R F D'Souza, N Fleming, K M Mellor, T L Merry.

Interleukin-6 (IL-6) is produced and secreted by skeletal muscle cells during exercise and plays an important role in mediating metabolic responses to exercise. The promoter region of the IL-6 gene contains a common genetic variant (-174 G/C, rs1800795) which may alter responses to exercise training. To isolate the impact of this gene variant on exercise-induced IL-6 expression and skeletal muscle transcription responses following exercise we generated knock-in mice with a GG or variant CC genotype for the murine homolog of rs1800795. The overall gross metabolic phenotype of resting mice was similar between genotypes; however, following acute treadmill running the variant CC genotype was associated with a greater increase in skeletal muscle IL-6 mRNA and circulating IL-6. Furthermore, we observed that mice with the variant CC genotype exhibited sex-specific differences in skeletal muscle master metabolism regulatory genes, and had greater increases in genes controlling mitochondrial biogenesis in skeletal muscle post-exercise. However, there was no effect of genotype on exercise-induced skeletal muscle glycogen depletion, circulating free fatty acids, blood glucose and lactate production, or exercise-responsive gene expression in subcutaneous fat. These findings suggest that the IL-6 promoter variant -174 G/C may result in enhanced skeletal muscle adaptations in response to exercise training, and could mean that individuals with the 'C' allele may more readily gain improvements in metabolic health in response to exercise training.

Keywords: exercise; genetic variant; interleukin-6; metabolism; skeletal muscle

DOI: https://doi.org/10.1152/japplphysiol.00391.2024