How does mitochondria function contribute to aerobic performance enhancement in lizards?

Aims: Aerobic exercise typically enhances endurance across vertebrates so that chronically high energy demands can be met. Some known mechanisms of doing this include increases in red blood cell numbers, angiogenesis, muscle fiber adaptions, mitochondria biogenesis, and changes to cellular metabolism and oxidative phosphorylation. We used green anole lizards (Anolis carolinensis) to test for an effect of aerobic exercise on metabolism, mitochondria densities, and mitochondrial function. Methods: We first tested the response of green anoles to endurance training and pyrroloquinoline quinone (PQQ) supplementation, which has been shown to increase mitochondria biogenesis. We also conducted a mitochondrial stress test to determine how training affected mitochondrial function in skeletal muscle fibers. Results: Aerobic exercise led to increased endurance and decreased standard metabolic rate (SMR), while PQQ did not affect endurance and increased SMR. In a second experiment, aerobic exercise increased endurance and decreased resting metabolic rate (RMR) in both male and female green anoles. Higher counts of mitochondrial gene copies in trained lizards suggested additional mitochondria adaptations to achieve increased endurance and decreased metabolism. A mitochondrial stress test revealed no effect on baseline oxygen consumption rates of muscle fibers, but untrained lizards had higher maximal oxygen consumption rates with the addition of metabolic fuel. Conclusion: It is likely that trained lizards exhibited lower maximal oxygen consumption rates by developing higher mitochondria efficiency. This adaptation allows for high ATP demand to be met by making more ATP per oxygen molecule consumed. On the other hand, it is possible that untrained lizards prioritized limiting reactive oxygen species (ROS) production at rest, while sacrificing higher levels of proton leak and higher oxygen consumption rates when working to meet high ATP demand.

Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease.

INTRODUCTION: Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. METHODS: Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. RESULTS: Screening by tNGS revealed pathogenic variants in 14 known monogenic USD genes, accounting for 45 families (13.1%), 27 biallelic and 18 monoallelic, including 1 family with a copy number variant (CNV). Recurrent genes included the following: SLC34A3 (n = 13), CLDN16 (n = 8), CYP24A1 (n = 4), SLC34A1 (n = 3), SLC4A1 (n = 3), APRT (n = 2), CLDN19 (n = 2), HNF4A1 (n = 2), and KCNJ1 (n = 2), whereas ATP6V1B1, CASR, and SLC12A1 and missed CNVs in the PH genes AGXT and GRHPR accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. CONCLUSION: Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials.

Is zeaxanthin needed for desiccation tolerance? Sustained forms of thermal dissipation in tolerant versus sensitive bryophytes.

Desiccation tolerant (DT) plants engage and disengage sustained forms of energy dissipation in response to desiccation and rehydration. This project sought to characterize the role of zeaxanthin and thylakoid protein phosphorylation status in sustained energy dissipation during desiccation in bryophytes with varying DT. Tolerant (Polytrichum piliferum, Dicranum species, Calliergon stramineum) and sensitive (Grimmia species, Schistidium rivulare, Sphagnum species) moss were desiccated in darkness or natural light conditions for up to three weeks. Desiccation caused pronounced reductions in Fv /Fm in all cases which was enhanced by light exposure during desiccation. Desiccation in darkness resulted in no accumulation of Z in any species, however, in natural light conditions there was significant accumulation of Z in tolerant but not sensitive species. Desiccation in natural light, relative to darkness, resulted in more pronounced reductions in Fo in tolerant but not sensitive species. Recovery of Fv /Fm upon rehydration occurred in two phases, a rapid phase (minutes) and a slower phase (hours). Increased time of desiccation, and light exposure, resulted in a reduction in the rapid phase. Desiccation in light conditions resulted in some accumulation of the phosphorylated form of the major light harvesting trimer (LHCII). Data are consistent with two mechanisms of sustained quenching, neither of which requires Z. However, when desiccation occurs in natural light conditions, accumulation of Z likely contributes to one or both of the sustained forms of dissipation. Increases in LHCII phosphorylation during desiccation are consistent with increased connectivity between the photosystems. The absence of Z formation in sensitive species may contribute to their lack of desiccation tolerance.

Obesity reduces mammary epithelial cell TGFß1 activity through macrophage-mediated extracellular matrix remodeling.

Obesity is a risk factor for breast cancer in postmenopausal and high-risk premenopausal women. Changes within the obese breast microenvironment may increase breast cancer risk. Transforming growth factor beta-1 (TGFß1) is a major regulator of mammary epithelial stem/progenitor cells, and its activity is dysregulated under conditions of obesity. Using a high-fat diet model of obesity in mice and breast tissue from women, we observed that TGFß1 activity is reduced in breast epithelial cells in obesity. Breast ducts and lobules demonstrated increased decorin in the extracellular matrix (ECM) surrounding epithelial cells, and we observed that decorin and latent TGFß1 complexed together. Under conditions of obesity, macrophages expressed higher levels of decorin and were significantly increased in number surrounding breast epithelial cells. To investigate the relationship between macrophages and decorin expression, we treated obese mice with either IgG control or anti-F4/80 antibodies to deplete macrophages. Mice treated with anti-F4/80 antibodies demonstrated reduced decorin surrounding mammary ducts and enhanced TGFß1 activity within mammary epithelial cells. Given the role of TGFß1 as a tumor suppressor, reduced epithelial TGFß1 activity and enhanced TGFß1 within the ECM of obese mammary tissue may enhance breast cancer risk.