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1,558 results found. For more information, click each entry to expand.

1: Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals: retained advantage for the transwomen
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Posted 26 Sep 2019

Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals: retained advantage for the transwomen
30,656 downloads bioRxiv physiology

A Wiik, TR Lundberg, E Rullman, DP Andersson, M Holmberg, M Mandić, TB Brismar, O Dahlqvist Leinhard, S Chanpen, J Flanagan, S Arver, T Gustafsson

Objectives: This study explored the effects of gender-affirming treatment, which includes inhibition of endogenous sex hormones and replacement with cross-sex hormones, on muscle function, size and composition in 11 transwomen (TW) and 12 transmen (TM). Methods: Isokinetic knee extensor and flexor muscle strength was assessed at baseline (T00), 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement (T0), and 3 (T3) and 11 (T12) months after hormone replacement. In addition, at T00 and T12, we assessed lower-limb muscle volume using MRI, and cross-sectional area (CSA) and radiological density using CT. Results: Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps CSA (15%) and radiological density (6%). In TW, the corresponding parameters decreased by -5% (muscle volume) and -4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained or slightly increased in strength. Baseline muscle volume correlated highly with strength (R>0.75), yet the relative change in muscle volume and strength correlated only moderately (R=0.65 in TW and R=0.32 in TM). The absolute levels of muscle volume and knee extension strength after the intervention still favored the TW. Conclusion: Cross-sex hormone treatment markedly affects muscle strength, size and composition in transgender individuals. Despite the robust increases in muscle mass and strength in TM, the TW were still stronger and had more muscle mass following 12 months of treatment. These findings add new knowledge that could be relevant when evaluating transwomen's eligibility to compete in the women's category of athletic competitions.

2: An association between sexes of successive siblings in the data from Demographic and Health Survey program
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Posted 12 Nov 2015

An association between sexes of successive siblings in the data from Demographic and Health Survey program
29,579 downloads bioRxiv physiology

Mikhail Monakhov

The prediction of future child's sex is a question of keen public interest. The probability of having a child of either sex is close to 50%, although multiple factors may slightly change this value. Some demographic studies suggested that sex determination can be influenced by previous pregnancies, although this hypothesis was not commonly accepted. This paper explores the correlations between siblings' sexes using data from the Demographic and Health Survey program. In the sample of about 2,214,601 women (7,985,855 children), the frequencies of sibships with multiple siblings of the same sex were significantly higher than can be expected by chance. A formal modelling demonstrated that sexes of the children were dependent on three kinds of sex ratio variation: a variation between families (Lexian), a variation within a family (Poisson) and a variation contingent upon the sex of preceding sibling (Markovian). There was a positive correlation between the sexes of successive siblings (coefficient = 0.067, p < 0.001), i.e. a child was more likely to be of the same sex as its preceding sibling. This correlation could be caused by secondary sex ratio adjustment in utero since the effect was decreasing with the length of birth-to-birth interval, and the birth-to-birth interval was longer for siblings with unlike sex.

3: The high abortion cost of human reproduction
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Posted 18 Jul 2018

The high abortion cost of human reproduction
5,903 downloads bioRxiv physiology

William R. Rice

Information from many large data bases and published studies was integrated to estimate the age-specific spontaneous abortion rate in an economically-developed human population. Accuracy was tested with published data from a diverse array of studies. Spontaneous abortion was found to be: i) the predominant outcome of fertilization and ii) a natural and inevitable part of human reproduction at all ages. The decision to reproduce is inextricably coupled with the production of spontaneous abortions with high probability, and the decision to have a large family leads to many spontaneous abortions with virtual certainty. The lifetime number of spontaneous abortions was estimated for a canonical woman (constrained to have average age at marriage, first birth, inter-birth intervals, and family size) in two populations: one with and the other without effective birth control (including free access to elective abortions). Birth control was found to reduce lifetime abortions more than 6-fold.

4: How strongly does appetite counter weight loss? Quantification of the homeostatic control of human energy intake
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Posted 29 Apr 2016

How strongly does appetite counter weight loss? Quantification of the homeostatic control of human energy intake
3,618 downloads bioRxiv physiology

David Polidori, Arjun Sanghvi, Randy Seeley, Kevin D. Hall

Objective: To quantify the homeostatic feedback control of energy intake in response to long-term covert manipulation of energy balance in free-living humans. Methods: We used a validated mathematical method to calculate energy intake changes during a 52 week placebo-controlled trial in 153 patients treated with canagliflozin, a sodium glucose co-transporter inhibitor that increases urinary glucose excretion thereby resulting in weight loss without patients being directly aware of the energy deficit. We analyzed the relationship between the body weight time course and the calculated energy intake changes using principles from engineering control theory. Results: We discovered that weight loss leads to a proportional homeostatic drive to increase energy intake above baseline by ~100 kcal/day per kg of lost weight - an amount more than 3-fold larger than the corresponding energy expenditure adaptations. Conclusions: While energy expenditure adaptations are often thought to be the main reason for slowing of weight loss and subsequent regain, feedback control of energy intake plays an even larger role and helps explain why long-term maintenance of a reduced body weight is so difficult.

5: First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus)
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Posted 03 Jun 2016

First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus)
3,172 downloads bioRxiv physiology

N. Bellofiore, S. Ellery, J. Mamrot, D. Walker, P. Temple-Smith, H. Dickinson

Background: Advances in research relating to menstruation and associated disorders (such as endometriosis and pre-menstrual syndrome) have been hindered by the lack of an appropriate animal model. Thus, many aspects of this phenomenon remain poorly understood limiting the development of efficacious treatment for women. Menstruating species account for only 1.5% of mammals, and less than 0.09% of these are non-primates. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents. Objective: Here we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus). Study Design: Virgin female spiny mice (n=14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles in our in-house colony at Monash Medical Centre, Clayton, Australia. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and ELISA assay of progesterone (n=5 / stage of the menstrual cycle). Normally distributed data are reported as the mean ± standard error and significant differences calculated using a one-way ANOVA. Non-normal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test. Results: Mean cycle length was 8.7 ± 0.4 days with red blood cells observed in the lavages over 3.0 ± 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase, when plasma progesterone peaked at ~102.1 ng/mL and the optical density for prolactin immunoreactivity was strongest. The spiny mouse undergoes spontaneous decidualisation, demonstrating for the first time menstruation in a rodent. Conclusion: The spiny mouse is the first rodent species known to menstruate and provides an unprecedented natural non-primate model to study the mechanisms of menstrual shedding and repair, and may be useful in furthering our understanding of human specific menstrual and pregnancy associated diseases.

6: Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.
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Posted 03 Dec 2019

Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.
3,129 downloads bioRxiv physiology

Lilia Espada, Alexander Dakhovnik, Prerana Chaudhari, Asya Martirosyan, Laura Miek, Tetiana Poliezhaieva, Yvonne Schaub, Ashish Nair, Nadia Döring, Norman Rahnis, Oliver Werz, Andreas Koeberle, Joanna Kirkpatrick, Alessandro Ori, Maria A. Ermolaeva

The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented.

7: Carbs versus fat: does it really matter for maintaining lost weight?
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Posted 28 Nov 2018

Carbs versus fat: does it really matter for maintaining lost weight?
3,122 downloads bioRxiv physiology

Kevin D. Hall, Juen Guo

The most read article of 2018 published in The BMJ (https://doi.org/10.1136/bmj.k4583) claimed that restricting dietary carbohydrates offers a metabolic advantage to burn more calories and thereby help patients maintain lost weight. However, analyzing the data according to the original pre-registered statistical plan resulted in no statistically significant effects of diet composition on energy expenditure. The large reported diet effects on energy expenditure calculated using the revised analysis plan depended on data from subjects with excessive amounts of unaccounted energy. Adjusting the data to be commensurate with energy conservation resulted in a diet effect that was less than half the value reported in The BMJ paper. Furthermore, the measured daily average CO2 production rates were not significantly different between the diets and the reported expenditure differences were due to inaccurate calculations based on false assumptions about diet adherence.

8: Multiple human adipocyte subtypes and mechanisms of their development
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Posted 31 Jan 2019

Multiple human adipocyte subtypes and mechanisms of their development
2,642 downloads bioRxiv physiology

So Yun Min, Anand Desai, Zinger Yang, Agastya Sharma, Ryan M.J. Genga, Alper Kucukural, Lawrence Lifshitz, Rene Maehr, Manuel Garber, Silvia Corvera

Human adipose tissue depots perform numerous diverse physiological functions, and are differentially linked to metabolic disease risk, yet only two major human adipocyte subtypes have been described, white and brown/brite/beige. The diversity and lineages of adipocyte classes have been studied in mice using genetic methods that cannot be applied in humans. Here we circumvent this problem by studying the fate of single mesenchymal progenitor cells obtained from human adipose tissue. We report that a minimum of four human adipocyte subtypes can be distinguished by transcriptomic analysis, specialized for functionally distinct processes such as adipokine secretion and thermogenesis. Evidence for the presence of these adipocytes subtypes in adult humans is evidenced by differential expression of key adipokines leptin and adiponectin in isolated mature adipocytes. The human adipocytes most similar to the mouse brite/beige adipocytes are enriched in mechanisms that promote iron accumulation and protect from oxidative stress, and are derived from progenitors that express high levels of cytokines such as IL1B, IL8, IL11 and the IL6 family cytokine LIF, and low levels of the transcriptional repressors ID1 and ID3. Our finding of this adipocyte repertoire and its developmental mechanisms provides a high-resolution framework to analyze human adipose tissue architecture and its role in systemic metabolism and metabolic disease.

9: Prevalence estimate of blood doping in elite track and field at the introduction of the Athlete Biological Passport
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Posted 19 Aug 2019

Prevalence estimate of blood doping in elite track and field at the introduction of the Athlete Biological Passport
2,628 downloads bioRxiv physiology

Faiss Raphael, Jonas Saugy, Alix Zollinger, Neil Robinson, Frédéric Schütz, Martial Saugy, Pierre-Yves Garnier

In elite sport, the Athlete Biological Passport (ABP) was invented to tackle cheaters by monitoring closely changes in biological parameters, flagging atypical variations. The haematological module of the ABP was indeed adopted in 2011 by the International Association of Athletics Federations (IAAF). This study estimates the prevalence of blood doping based on haematological parameters in a large cohort of track & field athletes measured at two international major events (2011 & 2013 IAAF World Championships) with a hypothesized decrease in prevalence due to the ABP introduction. A total of 3683 blood samples were collected and analysed from all participating athletes originating from 209 countries. The estimate of doping prevalence was obtained by using a Bayesian network with seven variables, as well as doping as a variable mimicking doping with low-doses of recombinant human erythropoietin (rhEPO), to generate reference cumulative distribution functions (CDFs) for the Abnormal Blood Profile Score (ABPS) from the ABP. Our results from robust haematological parameters indicate an estimation of an overall blood doping prevalence of 18% in average in endurance athletes (95% Confidence Interval (C.I.) 14-22%). A higher prevalence was observed in female athletes (22%, C.I. 16-28%) than in male athletes (15%, C.I. 9-20%). In conclusion, this study presents the first comparison of blood doping prevalence in elite athletes based on biological measurements from major international events that may help scientists and experts to use the ABP in a more efficient and deterrent way.

10: Connecting the legs with a spring improves human running economy
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Posted 30 Nov 2018

Connecting the legs with a spring improves human running economy
2,170 downloads bioRxiv physiology

Cole S. Simpson, Cara G. Welker, Scott D. Uhlrich, Sean M. Sketch, Rachel W Jackson, Scott L Delp, Steve H. Collins, Jessica C. Selinger, Elliot W. Hawkes

Spring-like tissues attached to the swinging legs of animals are thought to improve running economy by simply reducing the effort of leg swing. Here we show that a spring, or 'exotendon,' connecting the legs of a human runner improves economy instead through a more complex mechanism that produces savings during both swing and stance. The spring increases the energy optimal stride frequency; when runners adopt this new gait pattern, savings occur in both phases of gait. Remarkably, the simple device improves running economy by 6.4 ± 2.8%, comparable to savings achieved by motorized assistive robotics that directly target the costlier stance phase of gait. Our results highlight the importance of considering both the dynamics of the body and the adaptive strategies of the user when designing systems that couple human and machine.

11: Effects of diet on plumage coloration and pigment deposition in red and yellow domestic canaries
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Posted 24 Sep 2015

Effects of diet on plumage coloration and pigment deposition in red and yellow domestic canaries
2,091 downloads bioRxiv physiology

Rebecca Koch, Kevin J. McGraw, Geoffrey E. Hill

The Atlantic Canary (Serinus canaria) is the most common caged bird with extensive carotenoid plumage coloration. Domestic strains of canaries have been bred for a range of colors and patterns, making them a valuable model for studies of the genetic bases for feather pigmentation. However, no detailed account has been published on the feather pigments of the various strains of this species, particularly in relation to dietary pigments available during molt. Moreover, in the twentieth century, aviculturists created a red canary by crossing Atlantic Canaries with Red Siskins (Carduelis cucullata). This red-factor canary is reputed to metabolically transform yellow dietary pigments into red ketocarotenoids, but such metabolic capacity has yet to be documented in controlled experiments. We fed molting yellow and red-factor canaries seed diets supplemented with either B-carotene, lutein/zeaxanthin, or B-cryptoxanthin/B-carotene and measured the coloration and carotenoid content of newly grown feathers. On all diets, yellow canaries grew yellow feathers and red canaries grew red feathers. Yellow canaries deposited dietary pigments and metabolically derived canary xanthophylls into feathers. Red-factor canaries deposited the same plumage carotenoids as yellow canaries, but also deposited red ketocarotenoids. Red-factor canaries deposited higher total amounts of carotenoids than yellow canaries, but otherwise there was little effect of diet treatment on feather hue or chroma. These observations indicate that canaries can use a variety of dietary precursors to produce plumage coloration and that red canaries can metabolically convert yellow dietary carotenoids into red ketocarotenoids.

12: Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2
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Posted 21 Apr 2020

Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2
2,040 downloads bioRxiv physiology

Mehdi Baratchian, Jeffrey M. McManus, Mike Berk, Fumihiko Nakamura, Sanjay Mukhopadhyay, Weiling Xu, Serpil Erzurum, Judy Drazba, John Peterson, Eric A. Klein, Ben Gaston, Nima Sharifi

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide therapy. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance. ### Competing Interest Statement The authors have declared no competing interest.

13: Weight Loss in Response to Food Deprivation Predicts The Extent of Diet Induced Obesity in C57BL/6J Mice
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Posted 17 Apr 2014

Weight Loss in Response to Food Deprivation Predicts The Extent of Diet Induced Obesity in C57BL/6J Mice
2,019 downloads bioRxiv physiology

Matthew J. Peloquin, Dave Bridges

Inbred C57BL/6J mice have been used to study diet-induced obesity and the detrimental physiological effects associated with it. Little is understood about predictive factors that predispose an animal to weight gain. To address this, mice were fed a high fat diet, control diet or normal chow diet. Several measurements including pre-diet serum hormone levels and pre-diet body weight were analyzed, but these had limited predictive value regarding weight gain. However, baseline measurements of weight loss in response to food deprivation showed a strong negative correlation with high fat diet-induced weight gain. These data suggest that fasting-induced weight loss in adolescent mice is a useful predictor of diet-induced weight gain.

14: Adipocyte Jak2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance
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Posted 20 Sep 2016

Adipocyte Jak2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance
1,973 downloads bioRxiv physiology

Kevin C. Corbit, João Paulo G. Camporez, Jennifer L. Tran, Camella G. Wilson, Dylan Lowe, Sarah Nordstrom, Kirthana Ganeshan, Rachel J Perry, Gerald I. Shulman, Michael J Jurczak, Ethan J. Weiss

For nearly 100 years, Growth Hormone (GH) has been known to impact insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extra-hepatic, adipose tissue-dependent mechanism.

15: Proteomics of protein trafficking by in vivo tissue-specific labeling
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Posted 16 Apr 2020

Proteomics of protein trafficking by in vivo tissue-specific labeling
1,917 downloads bioRxiv physiology

Ilia A. Droujinine, Dan Wang, Yanhui Hu, Namrata D Udeshi, Luye Mu, Tanya Svinkina, Rebecca Zeng, Tess Branon, Areya Tabatabai, Justin A Bosch, John M Asara, Alice Y Ting, Steven A Carr, Norbert Perrimon

Secreted interorgan communication factors encode key regulators of homeostasis. However, long-standing questions surround their origins/destinations, mechanisms of interactions, and the number of proteins involved. Progress has been hindered by the lack of methodologies for these factors' large-scale identification and characterization, as conventional approaches cannot identify low-abundance factors and the origins and destinations of secreted proteins. We established an in vivo platform to investigate secreted protein trafficking between organs proteome-wide, whereby engineered promiscuous biotin ligase BirA*G3 (a relative of TurboID) biotinylates all proteins in a subcellular compartment of one tissue, and biotinylated proteins are affinity-enriched and identified from distal organs using quantitative mass spectrometry. Using this platform, we identified 51 putative muscle-secreted proteins from heads and 269 fat body-secreted proteins from legs/muscles, of which 60-70% have human orthologs. We demonstrate, in particular, that conserved fat body-derived novel interorgan communication factors CG31326, CG2145, and CG4332 promote muscle activity. Our results indicate that the communication network of secreted proteins is vast, and we identified systemic functions for a number of these factors. This approach is widely applicable to studies in interorgan, local and intracellular protein trafficking networks, non-conventional secretion, and to mammalian systems, under healthy or diseased states. ### Competing Interest Statement The authors have declared no competing interest.

16: Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways
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Posted 27 Jan 2018

Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways
1,718 downloads bioRxiv physiology

Kent Miner, Katja Labitzke, Benxian Liu, Paul Wang, Kathryn Henckels, Kevin Gaida, Robin Elliott, Jian Jeffrey Chen, Longbin Liu, Anh Leith, Esther Trueblood, Kelly Hensley, Xing-Zhong Xia, Oliver Homann, Brian Bennett, Mike Fiorino, John Whoriskey, Gang Yu, Sabine Escobar, Min Wong, Teresa L. Born, Alison Budelsky, Mike Comeau, Dirk Smith, Jonathan Phillips, James A. Johnston, Joe McGivern, Kerstin Weikl, David Powers, Karl Kunzelmann, Deanna Mohn, Andreas Hochheimer, John K. Sullivan

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor beta-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated-Cl- channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ~580,000 compounds. The anthelmintics niclosamide, nitazoxanide and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting beta-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully (>92%) bronchodilated airways, while the beta-agonist isoproterenol showed only partial (26-43%) effects. TMEM16A antagonists and repositioning of niclosamide or nitazoxanide could represent an important additional treatment for uncontrolled severe disease.

17: Aged-senescent cells contribute to impaired heart regeneration
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Posted 21 Aug 2018

Aged-senescent cells contribute to impaired heart regeneration
1,617 downloads bioRxiv physiology

Fiona C Lewis-McDougall, Prashant J Ruchaya, Eva Domenjo-Vila, Tze Shin Teoh, Larissa Prata, Beverley J Cottle, James E Clark, Prakash P Punjabi, Wael Awad, Daniele Torella, Tamara Tchkonia, James L Kirkland, Georgina M Ellison-Hughes

Rationale: Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Objective: To determine the impact of ageing and senescence on human cardiac stem/progenitor cell (CPC) biology and regenerative potential, and investigate whether elimination of senescent cells in aged mice enhances CPC activation and cardiomyocyte proliferation. Methods and Results: CPCs were isolated from the right atrial appendage (~200mg) of human subjects with cardiovascular disease (n=119), aged 32-86 years, and assessed for expression of senescence-associated markers (p16INK4A, SAbetagal, DNA damage yH2AX, telomere length), Senescence-Associated Secretory Phenotype (SASP), cell growth, differentiation, and regenerative potential following transplantation into the infarcted mouse heart. Senescent cells were eliminated in aged mice (22 to 32 months) in vivo either genetically, using INK-ATTAC mice, which results in inducible elimination of p16Ink4a-expressing senescent cells upon the administration of the drug AP20187, or pharmacologically using intermittent oral administration of combined senolytics, Dasatinib (D) and Quercetin (Q). In aged subjects (>74 years old) over half of CPCs are senescent, unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. Aged-senescent CPCs secrete SASP factors, which renders otherwise healthy, cycling-competent CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q) in vivo activates resident CPCs (0.23±0.06% vs. 0.01±0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25±0.07% vs. 0.03±0.03% vehicle; p<0.05). Conclusions: Human CPCs become senescent with age, negatively impacting their regenerative capacity. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

18: Age and life expectancy clocks based on machine learning analysis of mouse frailty
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Posted 23 Dec 2019

Age and life expectancy clocks based on machine learning analysis of mouse frailty
1,579 downloads bioRxiv physiology

Michael B. Schultz, Alice E Kane, Sarah J. Mitchell, Michael R MacArthur, Elisa Warner, James R Mitchell, Susan E Howlett, Michael S. Bonkowski, David A. Sinclair

The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs were scored longitudinally until death and machine learning was employed to develop two clocks. A random forest regression was trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model was trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of novel longevity genes and aging interventions.

19: Insulin-like growth factor 1 receptor signaling in tenocytes is required for adult tendon growth
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Posted 13 Jun 2019

Insulin-like growth factor 1 receptor signaling in tenocytes is required for adult tendon growth
1,493 downloads bioRxiv physiology

Nathaniel P Disser, Kristoffer B Sugg, Jeffrey R. Talarek, Dylan C. Sarver, Brennan J Rourke, Christopher L Mendias

Tenocytes serve to synthesize and maintain collagen fibrils and other matrix proteins in tendon. The underlying biological mechanisms of postnatal tendon growth and repair are not well understood. Insulin-like growth factor 1 (IGF1) plays an important role in the growth and remodeling of numerous tissues, but less is known about IGF1 in tendon. We hypothesized that IGF1 signaling is required for proper tendon growth in response to mechanical loading through regulation of collagen synthesis and cell proliferation. We conditionally deleted the IGF1 receptor ( IGF1R ) in scleraxis ( Scx ) expressing tenocytes, and compared to control Scx:IGF1R + mice, Scx:IGF1R Δ mice demonstrated reduced tenocyte proliferation and smaller tendons in response to mechanical loading. Additionally, we identified that both the PI3K/Akt and ERK pathways are activated downstream of IGF1 and interact in a coordinated manner to regulate cell proliferation and protein synthesis. These studies indicate that IGF1 signaling is required for proper postnatal tendon growth.

20: Thermoneutrality induces skeletal muscle myopathy via brown adipose tissue in an IRF4- and myostatin-dependent manner
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Posted 02 Mar 2018

Thermoneutrality induces skeletal muscle myopathy via brown adipose tissue in an IRF4- and myostatin-dependent manner
1,485 downloads bioRxiv physiology

Xingxing Kong, Peng Zhou, Ting Yao, Lawrence Kazak, Danielle Tenen, Anna Lyubetskaya, Brian A. Dawes, Linus Tsai, Barbara B. Kahn, Bruce M. Spiegelman, Tiemin Liu, Evan D Rosen

Skeletal muscle and brown adipose tissue (BAT) share a common lineage and have been functionally linked, as exercise increases browning through the actions of various myokines. It is unknown, however, whether BAT can affect skeletal muscle function. Our prior work has shown that loss of the transcription factor IRF4 in BAT (BATI4KO) reduces adaptive thermogenesis. Here, we note that these mice also have reduced exercise capacity relative to wild-type littermates, associated with diminished mitochondrial function, ribosomal protein synthesis, and mTOR signaling in muscle, in addition to the signature ultrastructural abnormalities of tubular aggregate myopathy. Within brown adipose tissue, loss of IRF4 caused the induction of a myogenic gene expression signature, which includes an increase in the secreted factor myostatin, a known inhibitor of muscle function. Reduction of myostatin activity by the injection of neutralizing antibodies or soluble ActRIIB receptor rescued the exercise capacity of BATI4KO mice. Additionally, overexpression of IRF4 in brown adipocytes reduced serum myostatin and increased mitochondrial function and exercise capacity in muscle. A physiological role for this system is suggested by the observation that mice housed at thermoneutrality show lower exercise capacity with increased serum myostatin; both of these abnormalities are corrected by surgical removal of BAT. Collectively, our data point to an unsuspected level of BAT-muscle cross-talk driven by IRF4 and myostatin.

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