Physiology

Evaluation Summary:

The effective approach for targeting select subsets of enteroendocrine cells described here will be important for neuroscientists, endocrinologists, microbiologists, and other scientists studying nutritional biology. The study reveals new detail of how enteroendocrine cells signal through spinal and vagal sensory neurons to control immediate behavior and to guide learning about potential food sources. Overall, the approach is well thought out and the results are interesting and unexpected.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

eLife assessment

McKay, et al. describe development of a new wireless, network-enabled automated feeder system with which diet amount and schedule can be controlled across individually housed killifish. The system is constructed using open-source components and software and is amenable to manufacture by individual research groups and is highly scalable. The authors then use this system to explore dietary restriction effects on killifish lifespan and to develop an associative learning assay, two important goals in the KF /longevity field. The authors demonstrate that precise control of food allows automated investigation of lifespan extension under calorie restriction conditions. Secondly, they show an exciting modification of the system that involves only addition of a simple LED light. This modification allows use of the system in an associative learning / conditioning paradigm. Finally, using this paradigm, they demonstrate an age-dependent decline in learning.

eLife assessment

The purpose of the study was to evaluate the transcription factor NF-kB, a common transcription factor that is thought to mediate muscle atrophy, in the setting of a rotator cuff injury. The authors used gain of function and loss of function NF-kB inhibitors to show that, surprisingly, NF-kB does not seem to be a major mediator of muscle atrophy in this model (as compared to other atrophy models), but there are sex-related differences. They found that male mice were more likely to have atrophy regulated by autophagy, both of which are interesting, novel findings.

eLife Assessment:

This manuscript presents a biophysical study of the nature of the mechanosensitivity of voltage-gated sodium channels. The identification of a voltage-independent mechanosensitive step is well founded, the proposal that this step is the intracellular gate is plausible speculation. It is expected to be of interest to scientists studying the physical basis of mechanosensitivity in electrophysiology.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This is an important and delicately designed study that uses integrated tools to reveal underlying mechanisms of repair of the endometrium at menstruation. It combines single cell sequencing analysis and lineage tracing technologies to strongly prove that repair-specific cells originate from the fibroblast cell clusters and PDGFRα+ endometrial fibroblasts undergo MET and can become incorporated into the luminal epithelium of the post repair tissue.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript examines the importance of PKA-dependent mTORC1 activation for the weight-loss effects of liraglutide. The work has the potential to provide important insights, but at present is deemed preliminary as it lacks details on the mouse model and control data and needs a more in-depth analysis of the metabolic phenotype.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

The study is overall well-planned and the amount of data presented by the authors is impressive. The work nicely incorporates animal-level physiology (echocardiography data), tests for known canonical markers of hypertrophy, and then delves into an unbiased analysis of the transcriptome and proteome of LV tissue in bulk. The techniques and analyses in the study are adequately executed and within the realm of expertise of the Lakatta laboratory. This study is a necessary and crucial first step to extensively phenotype this mouse line and generate hypotheses for further work.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript is of broad interest to researchers working in the area of lower urinary tract dysfunction. It describes a novel method to reliably study bladder function; the approach allows for monitoring bladder filling and emptying in freely moving, non-anaesthetized animals without the need for catheter implantation. This work has optimized a machine learning algorithm for defining the outline of the urinary bladder border from fluoroscopic images of mice that received subcutaneous injections of iodinated radiocontrast media. The advantage is that with images taken at 30 images/second and with monitoring bladder dynamics requiring hours-long observation periods, this very large number of generated images no longer requires manual analysis.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript will be of broad interest to the field of muscle biology, muscle physiology, exercise physiology, metabolism and circadian rhythms. This manuscript identifies a new molecular pathway that connects circadian rhythms to muscle structure and function through titin isoform switching.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The manuscript by Yue et al describes studies investigating the role of sensory neuron versus arteriole expression of Trpv1 in body temperature control. This is a detail about the contribution of different cells which has significance because of the reported on-target side-effect of hyperthermia by Trpv1-antagonists. The study shows that the effects on body temperature are predominantly produced through sensory neurons. From these studies it is speculated that the actions of Trpv1 might be pharmacologically modified to permit dissociation of the effects on neurogenic inflammation and the undesirable effects on body temperature.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. All reviewers agreed to share their names with the authors.)

Evaluation Summary:

This study evaluates the effects of two distinct dietary methods that cause obesity in mice (high fat vs high starch) on insulin sensitivity and glucose homeostasis. Through a series of nicely performed physiology experiments, the authors demonstrated that high starch feeding causes obesity without deleterious effects on insulin sensitivity. This work will have an impact in the field and help define the important lipid mediators of metabolic disease.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Monteiro de Assis et al. demonstrate a role for T3 in modulating circadian metabolic rhythms both systemically and within the liver. The findings extend the molecular framework in which organismal metabolism is coordinated in a circadian fashion.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors provide novel evidence that semaphorin signaling (SEMA3F) is engaged in the vascular endothelium and smooth muscle to confer atheroprotection. They show that SEMA3F reduces the activity of key enzyme Phosphoinositide 3-kinase to decrease smooth muscle cell proliferation, migration, and phenotype switching, which contributes to atheroprotection. The study has significant translational potential and yields a new therapeutic target.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The authors have used two transgenic mouse models expressing dominant negative Cx43 mutants to evaluate the role of Cx43 hemichannels in mechanical loading response in bone. While understanding the molecular mechanisms by which osteocytes respond to mechanical strain is of interest in the skeletal biology arena, the conclusions of this study are not fully supported by experimental data and are of only incremental in nature.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript.The reviewers remained anonymous to the authors.)

Evaluation Summary:

The study of previously unexplored roles of a cytoskeleton protein termed Septin-7 in muscle could be a significant contribution to understand muscle development and regeneration. The majority of the data support the importance of Septin-7 protein in muscle physiology. With some additional experiments and data analysis to strengthen the mechanistic characterization of Septin-7 in muscle physiology, this manuscript will be of broad interest to readers in the skeletal muscle research field.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors have systematically examined relationships between muscle length and force potentiation in young adults using very carefully conducted and controlled measurements by dynamometry and estimated using patellar tendon shear wave speed. The paper should be of interest to those who study human performance.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The TRPV2 channel plays essential roles in many cell types in the body, including macrophages and cardiomyocytes, but its physiological mechanisms of activation and regulation remain largely unknown. Mo and collaborators describe a novel regulatory mechanism of TRPV2 channels in which phosphorylation at three different tyrosine residues by JAK1 sensitizes channels to activation by 2-APB and heat, whereas de-phosphorylation by PTPN1 reverses sensitization. Changes in the dynamics of TRPV2 channel phosphorylation could have important physiological consequences in many cell types expressing these channels. The data are of significant importance for the scientific community interested in function und relevance of transient receptor potential ion channels.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

It is becoming increasingly clear that adipocytes are not homogenous, but rather comprise several distinct subtypes with specific physiological functions. This work presents evidence for the surprising finding of a subpopulation of adipocytes displaying non-canonical Wnt signaling. The possible role of these adipocytes in thermogenesis is more ambiguous, and their physiological function remains unclear.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study analyzed muscle protein differences between octogenarian master athletes and non-athletes. The data showed that high physical function in octogenarians was associated with the increased mitochondrial proteome, reduced number of muscle fibers impaired by oxphos, and higher mtDNA copy number. The authors propose that this is one of the mechanisms contributing to better performance in master athletes compared with non-athletes, suggesting that mitochondrial health in skeletal muscle is a key feature in inducing improved physical function in the elderly. This article has the potential to generate a significant impact within the field and will be of interest to a broad audience.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study reports new post-translational modifications (PTMs) to β-myosin heavy chain, using tissue samples from normal and failing human hearts. Atomistic simulations of myosin molecular dynamics suggest that these PTMs lead to meaningful alterations in structure, solvent exposure, and dynamics of certain regions of the protein. These data and simulations provide a foundation for further work to determine the precise functional significance of β-myosin heavy chain PTMs. The work will be of interest to cell biologists and cardiologists.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)