Physiology

eLife assessment

This important study investigates, from Drosophila to mammals, the role of the Forkhead box O (FoxO) transcription factors in airway epithelial cells' response to stressors including hypoxia, temperature variations, and oxidative stress. The findings suggest a conserved role of FoxO in maintaining airway homeostasis across species. However, limitations in the specificity and concerns with the loss-of-function experiments render the evidence presented incomplete. Nonetheless, this study highlights FoxO's potential relevance in respiratory diseases like asthma and offers insights into potential therapeutic targets for conditions affecting airway health.

eLife assessment

Using in vitro and in vivo experiments, the authors show that astrocytes swell after inhibition of aquaporin 4 (AQP4) with TGN-020, which is indicative of tonic water efflux from these cells under physiological conditions. Though potentially valuable, the study is currently incomplete due to possible off-target effects of TGN-020, limited mechanistic information underlying the detected effects, and potential limitations of some of the adopted experimental techniques. These findings can be especially relevant for cortical spreading depression in ischemic stroke or seizure and to get a comprehensive understanding of neuron-astrocyte interactions.

eLife assessment

This study provides valuable information on how Arg-II participates in cardiac aging. Although the phenotypic data appear robust, the study is incomplete in elucidating the mechanisms, particularly in explaining how Arg II influences IL-1b and affects cardiac aging. It would be beneficial to investigate the possibility of NO involvement in this mice model. A co-culture system may be required to understand the non-cell-autonomous functions of macrophages. Lastly, the MI mouse model may not be directly linked to cardiac aging.

eLife assessment

This study unveils important mechanistic insights into postnatal lung development and bronchopulmonary dysplasia (BPD) pathology. Using two BPD models enhances our comprehension of the disease, utilizing compelling evidence from single-cell sequencing and flow cytometry, revealing a myofibroblast loss. Pharmacological and genetic approaches convincingly argue against the presumed increase in TGFb signaling causing alveolar simplification; instead, it appears to be a compensatory response. The identified weakness is the absence of validation in tissue, leaving the question unanswered regarding whether myofibroblast loss is due to a lack of myofibroblast proliferation or myofibroblast differentiation/specification.

eLife assessment

The work by Lewis and co-workers presents important findings on the role of myosin structure/energetics on the molecular mechanisms of hibernation by comparing muscle samples from small and large hibernating mammals. The solid methodological approaches have revealed insights into the mechanisms of non-shivering thermogenesis and energy expenditure.

eLife assessment

This important study, using three bioactive compounds as a model, demonstrates that estimating the intake of food components based on food composition databases and self-reported dietary data is highly unreliable. The authors present convincing data showing the differences in the estimated quantile of intake of three bioactive compounds between biomarker and 24-hour dietary recall with food-composition database. The work will be of broad interest to the clinical nutrition research community.

eLife assessment

This manuscript presents a detailed characterization of male and female wild-type and CTRP10 knockout mice, revealing that knockout mice develop female-specific obesity that is largely uncoupled from metabolic dysfunction. The data are convincing, and the work is a valuable contribution to understanding how obesity is coupled to metabolic dysfunction, and how this can occur in a sex-specific manner.

eLife assessment

This study presents important findings on long-lived proteins in the mouse ovary and oocytes. Convincing evidence using two-generation stable isotope-based metabolic labelling of mice in combination with mass spectrometry analysis describes a resource of enriched long-lived macromolecules in oocytes and somatic cells. Mitochondrial, cytoskeletal, and myosin proteins were identified as long-lived. While this is a unique resource with significant value in the understanding of female reproductive aging, the results would be strengthened if supported by an orthogonal validation and a more in-depth mechanistic explanation of the relationship between mitochondrial and cytoskeletal protein stability and aging.

eLife assessment

Using unbiased transcriptional profiling, the study reports a fundamental discovery of a novel hepatic lncRNA, FincoR, which regulates FXR. The convincing findings have therapeutic implications in the treatment of MASH. The authors use state-of-the-art methodology and use unbiased transcriptomic profiling and epigenetic profiling, including validation in mouse models and human samples.

eLife assessment

TRPV4 is a unique cation channel that has been demonstrated to play a role in a variety of sensory processes. The authors provide useful new data to indicate that TRPV4 activation occurs in eccrine gland cells. They then show that temperature-dependent perspiration is TRPV4-dependent in mouse skin. This provides new insight, but the data are incomplete in that more orthogonal assays could be used to more comprehensively support the conclusions.

eLife assessment

This is a compelling study on pro-inflammatory and anti-inflammatory lipids in relation to skeletal muscle injury. It convincingly identifies pro-inflammatory lipids during recovery predisposing to fibrosis, and maresin 1 as an anti-inflammatory lipid reducing fibrosis, improved muscle regeneration, partially restoring contractile function, of fundamental potential clinical application.

eLife assessment

The study presents valuable findings on sexually dimorphic patterns of osteocytic transcriptomes and low calcium diet-induced osteocytic osteolysis in FNDC5-deficient mice. The authors present solid evidence for sex-specific changes in osteocyte morphology and gene expression under a calcium-demanding setting in this particular strain of mice, although the protective role of FNDC5-deficiency in lactation and low-calcium diet in female mice remains unclear due to lack of mechanistic studies. The study also lacks evidence that irisin, a proteolytically cleaved product of FNDC5, is responsible for the observed phenotypes, as irisin was not directly measured.

eLife assessment

The study presents valuable findings on compensatory mechanisms in response to glycosuria. The evidence supporting the claims is solid, although a causal relationship is somewhat uncertain and the addition of a more clinically relevant model would have strengthened the findings. The work will be of interest to diabetes investigators.

eLife assessment

This work describes a connection between inflammation and metabolism, in which itaconate stabilizes the mitochondrial fatty acid uptake enzyme Cpt1a to enhance fatty acid oxidation. The mechanism for itaconate action may be generalizable to other protein targets. This is an important advance, which is supported by solid experimental data.

eLife assessment

The work by Johnson and co-workers has identified an important role of 2-Hydroxybutyrate in skeletal muscle oxidative capacity in the early stages of exercise. Mechanistically, they show convincing data to support a role of 2-Hydroxybutyrate in the regulation of BCAA metabolism via SIRT4, ADP-Ribosylation, and CEBP. However, whether this is the sole mechanism and if these translate to longer exercise training regimes requires future experiments.

eLife assessment

This valuable study shows that auxin exposure perturbs feeding behavior, survival rates, lipid metabolism, and gene expression patterns in adult Drosophila flies. The results are solid with proper methods and data analyses, and the evidence broadly supports the conclusions with only minor weaknesses. This work is relevant for fly geneticists who are interested in using the auxin-inducible gene expression system for inducing target protein degradation acutely.

eLife assessment

This study presents valuable observations indicating that the electrophysiological excitability of cultured sympathetic motor neurons progressively increase during aging, and are inversely correlated with the magnitude of KCNQ currents. The alterations in membrane excitability are broadly relevant for those interested in understanding how the nervous system changes during aging. While the data as a whole are solid in showing that the excitability of sympathetic neurons increases in neurons cultured from older mice, the mechanism of the underlying changes and in vivo relevance is incomplete.

eLife assessment

This manuscript aims to identify the pacemaker cells in the lymphatic collecting vessels - the cells that initiate the autonomous action potentials and contractions needed to drive lymphatic pumping. Through the exemplary use of existing approaches (genetic deletions and cytosolic calcium detection in multiple cell types), the authors convincingly determine that lymphatic muscle cells are the origin of the action potential that triggers lymphatic contraction. This fundamental discovery establishes a new standard for the field of lymphatic physiology.

eLife assessment

This study presents a valuable finding on relationship between high protein diet and resistance exercise on fat accumulation and glucose homeostasis. The evidence supporting the claims of the authors is solid, although inclusion of mechanistic insight would have strengthened the study. The work will be of interest to dietician and exercise biologists working to understand the synergy between diet and physical activity.

eLife assessment

This study develops an important method for dissecting out two overlapping cell signaling pathways, phosphoinositide signaling and membrane protein trafficking. The combination of two state-of-the-art techniques provides compelling evidence for a reciprocal influence between an enzyme and a channel. The work will be of interest to the broader cell biology, biophysics and biochemistry communities.