Physiology

Probing relaxed myosin states in hypertrophic cardiomyopathy by second harmonic-generation microscopy

1. Giulia Arecchi
2. Marica Dente
3. Weikang Ma
4. Beatrice Scellini
5. Nicoletta Piroddi
6. Marina Scardigli
7. Jingyuan Yu
8. Jing Zhao
9. Riccardo Cicchi
10. Ryo Kinegawa
11. Caroline Muellenbroich
12. Francesco Sera
13. Corrado Poggesi
14. Cecilia Ferrantini
15. Thomas C Irving
16. Michael Regnier
17. Leonardo Sacconi
18. Chiara Tesi

• Curated by eLife

  eLife Assessment

  This fundamental study demonstrates that polarized second-harmonic generation microscopy can be used to probe the ON/OFF states of myosin in both permeabilized and intact muscle, making this key measurement accessible to a greater number of labs. This has the potential to help with the study of disease-causing mutations and our understanding of drug function. The methodology is well defined, and the results are convincing; however, there are some limitations to the interpretation of the data.

Reviewed by eLife

A whole-animal phenotypic drug screen identifies suppressors of atherogenic lipoproteins

1. Daniel J Kelpsch
2. Liyun Zhang
3. James H Thierer
4. Adrian G Rivera Cruz
5. Kobe Koren
6. Urmi Kumar
7. Yuki Lin
8. Monica R Hensley
9. Mira Sohn
10. Jun O Liu
11. Thomas Lectka
12. Jeff S Mumm
13. Steven A Farber

• Curated by eLife

  eLife Assessment

  In this important study, the authors have performed a zebrafish drug screen to identify suppressors of atherogenic lipoproteins. They utilize a well-established LipoGlo assay to find molecules that modulate these lipoproteins, identifying 49 potential hits and they perform validation experiments, including studies linking enoxolone to its likely inhibitory effect on a specific transcription factor, HNF4alpha. Overall, the results are convincing and robust, and will open up new areas of exploration for those investigators interested in in vivo lipid biology.

Reviewed by eLife

RiboTRAP-seq identifies spatially distinct functions for the anterior and posterior intestine in immune and metabolic regulation in C. elegans

1. Chung-Chih Liu
2. Nicolas Seban
3. Supriya Srinivasan

• Curated by eLife

  eLife Assessment

  In this valuable study, the authors performed cell-specific ribosome pulldown to identify gene expression (translatome) differences in the anterior (NT1) vs middle & posterior (NT2-9) cells of the C. elegans intestine, under fed, starved, or refeeding conditions. The data generated will be very helpful to the C. elegans community, and the evidence supporting the conclusions of the study is assessed to be solid. Some methodological caveats remain and are discussed.

Reviewed by eLife

Nfe2l1-mediated proteasome function controls muscle energy metabolism in obesity

1. Imke L. Lemmer
2. Daniel T. Haas
3. Nienke Willemsen
4. Stefan Kotschi
5. Irmak Toksöz
6. Ejona Gjika
7. Sajjad Khani
8. Maria Rohm
9. Nick Diercksen
10. Phong B.H. Nguyen
11. Michael P. Menden
12. Desalegn T. Egu
13. Jens Waschke
14. Steen Larsen
15. Tao Ma
16. Zachary Gerhart-Hines
17. Stephan Herzig
18. Kenneth Dyar
19. Natalie Krahmer
20. Alexander Bartelt

Reviewed by Review Commons

Sex-biased expression of enteroendocrine cell-derived hormones contributes to higher fat storage in Drosophila females

1. Puja Biswas
2. Elizabeth J Rideout

• Curated by eLife

  eLife Assessment

  This useful study provides a systematic comparison of sex-biased enteroendocrine hormone expression in Drosophila and suggests that gut-derived peptides may contribute to female-biased triglyceride levels. The revised manuscript includes helpful textual clarifications and an integrative model, but the evidence remains incomplete, because the proposed role of Tk is still over-interpreted relative to authors' stated criterion for statistical significance against both parental controls. The work will be of interest to researchers studying sex differences in metabolism, but the central mechanistic claims require either stronger experimental support or more careful qualification.

Reviewed by eLife

The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch

1. Robbert van der Pijl
2. Jochen Gohlke
3. Joshua Strom
4. Eva Peters
5. Shengyi Shen
6. Stefan Conijn
7. Zaynab Hourani
8. Stephan Lange
9. Ju Chen
10. Paul Langlais
11. Siegfried Labeit
12. Henk L Granzier
13. Coen Ottenheijm

• Curated by eLife

  eLife Assessment

  The work by van der Pijl presents important findings on the role of titin-associated muscle ankyrin repeat proteins (MARPs) on hypertrophy via mTOR signalling. The study presents rigourous data using in vivo loss-of-function and pharmacological approaches to investigate effects on hypertrophy. While the evidence supporting the role of MARPs on hypertrophy is solid, there are limitations. For example, the use of Rapamycin only inhibits some aspects of mTORC1 signalling and the study is limited to analysis of the diaphragm and thus it is not clear if the mechanisms are conserved across other muscle types.

Reviewed by eLife

Orco regulates the circadian activity of pheromone-sensitive olfactory receptor neurons in hawkmoths

1. Aditi Vijayan
2. Mauro Forlino
3. Yajun Chang
4. Pablo Rojas
5. Katrin Schröder
6. Anna C Schneider
7. Martin E Garcia
8. Monika Stengl

• Curated by eLife

  eLife Assessment

  This valuable study uses technically compelling long-term in vivo recordings and computational modeling to investigate whether hawkmoth olfactory receptor neurons show circadian modulation of spontaneous firing. The authors further propose the provocative model that post-translational mechanisms, rather than the transcriptional-translational processes, may contribute to circadian regulation of neuronal excitability. However, the evidence for circadian firing in these neurons, and for post-translational modification of Orco as the underlying mechanism, remains incomplete. In contrast, the study does provide strong evidence that the application of cyclic nucleotides can modulate Orco-dependent activity at a single time point, and reports that the temporal pattern of Orco transcript abundance is not circadian.

Reviewed by eLife

Exercise-Induced Hypoalgesia Following High- vs. Low-Intensity Aerobic Exercise in Fit Females

1. Janne I Nold
2. Tahmine Fadai
3. Zora P Gerbers
4. Christian Büchel

• Curated by eLife

  eLife Assessment

  This study proposes that fitness level influences exercise-induced hypoalgesia in women. However, the evidence to support this claim is incomplete: the conclusions rely on a small interaction that emerges only under specific conditions and are incongruent with the title, the findings are inconsistent across pain modalities and stimulus intensities, the analysis approach does not fully exploit the continuous pain ratings collected, and the absence of a baseline condition limits the interpretability of results as reflecting true hypoalgesia. Additionally, the methods by which fitness level was categorized across cohorts can be questioned, and the results and figures do not clearly illustrate how between-group comparisons were conducted. With a proper revision, it could be useful for sports medicine practitioners to consider how they administer exercise protocols to help those experiencing pain.

Reviewed by eLife

Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline

1. Sara C Sebag
2. Tate Neff
3. Qingwen Qian
4. Arvand Asghari
5. Zhuozhi Wang
6. Zeyuan Zhang
7. Mark Li
8. Meihua Hao
9. Vitor A Lira
10. Hongli Sun
11. Matthew J Potthoff
12. Ling Yang

• Curated by eLife

  eLife Assessment

  This valuable study identifies a brown adipose tissue-specific heat shock factor 1 (HSF1)-alcohol dehydrogenase 5 (ADH5) axis that regulates oxidative stress and cellular senescence during aging. The authors show that ADH5 deficiency drives BAT dysfunction and contributes to organismal health decline in aged mice. The evidence is convincing, and the work will be of broad interest to the adipose tissue and aging research communities.

Reviewed by eLife

NK2R signaling governs intestinal lipid mobilization and mucosal inflammation

1. Pedro A Perez
2. Chung-Chih Liu
3. Alessandra Ferrari
4. Nicole Littlejohn
5. John Paul Kennelly
6. Emma Robinson
7. Vân TB Nguyen-Tran
8. Jon Athanacio
9. Sean B Joseph
10. Zaid Amso
11. Peter Tontonoz
12. Supriya Srinivasan

• Curated by eLife

  eLife Assessment

  This is an important study on the role of the neurokinin-2 receptor (NK2R) as a regulatory node connecting intestinal lipid metabolism, mucosal immunity, and the gut microbiome, bidirectionally regulating enterocyte lipid uptake, lipid droplet storage, chylomicron output, and systemic metabolic parameters in DIO mice. The authors present solid evidence linking Tacr2 deletion to reprogrammed epithelial lineage allocation, dampened immune gene expression, and male-biased protection from DSS colitis, despite dysbiotic microbiota. However, the causal evidence for some mechanistic and pro-inflammatory NK2R claims remains incomplete and potentially confounding, requiring additional cell-type-specific and functional experiments.

Reviewed by eLife