Physiological genomics最新文献

Risk factors for cardiac arrhythmias that can cause sudden death and heart failure include genetics, age, lifestyle, and other environmental factors. The study assessed electrocardiography (ECG) traits in BXD mice and explored associated quantitative trait loci (QTLs). Five-minute electrocardiograms were recorded in 44 BXD strains at 4-5 mo of age (n ≥ 5 mice/sex/strain). ECG and arrhythmia traits were associated with echocardiography, blood pressure, genome, and heart transcriptome data followed by expression QTL mapping. A significant variability in ECG parameters and arrhythmias was recorded among BXDs. Among male BXDs, QRS duration was significantly associated with increased left ventricular internal diameter (LVID) and reduced ejection fraction and fractional shortening, whereas premature ventricular contractions (PVCs) were correlated with LVID, left ventricular (LV) volumes, and pulmonary vein peak pressure. In female BXDs, PVCs and premature atrial contractions (PACs) were significantly related with right ventricular ID and cardiac output. One significant QTL associated with QTc and JT durations was identified on Chromosome (Chr) 3 in male BXDs, whereas Chr 9 locus was suggestive for association with QTc and QT intervals in female mice. Gon4l was predicted as a strong candidate gene associated with repolarization abnormalities including short or long QT syndromes in humans. Study results suggested an influence of genetic background on expression of ECG parameters and arrhythmias based on significant variations of those traits between mouse strains of the BXD family. We conclude that murine BXD family can serve as a valuable reference for systems biology and comparative predictions of arrhythmia disorders.NEW & NOTEWORTHY Our study identified significant variances in ECG phenotypes and arrhythmias segregation in BXD mice. A significant quantitative trait locus (QTL) on Chromosome (Chr) 3 in the mouse genome was associated with increased QTc and JT intervals in male BXD mice. A suggestive QTL on Chr 9 associated with QT and QTc intervals was determined in female BXD mice. We identified a strong candidate gene, Gon4l, that may underlie cardiac repolarization abnormalities such as long and short QT syndromes.

Risk of cardiovascular disease (CVD) in women increases with the menopausal transition. Using a chemical model (4-vinylcyclohexene diepoxide; VCD) of accelerated ovarian failure, we previously demonstrated that menopausal females are more susceptible to CVD compared with peri- or premenopausal females like humans. Yet, the cellular and molecular mechanisms underlying this shift in CVD susceptibility across the pre- to peri- to menopause continuum remain understudied. In this work using the VCD mouse model, we phenotyped cellular and molecular signatures from hearts at each hormonally distinct stage that included transcriptomic, proteomic, and cell biological analyses. The transcriptional profile of premenopausal hearts clustered separately from perimenopausal and menopausal hearts, which clustered more similarly. Proteomics also revealed hormonal clustering; perimenopausal hearts grouped more closely with premenopausal than menopausal hearts. Both proteomes and transcriptomes showed similar trends in genes associated with atherothrombosis, contractility, and impaired nuclear signaling between pre-, peri-, and menopausal murine hearts. Further analysis of posttranslational modifications (PTMs) showed hormone-dependent shifts in the phosphoproteome and acetylome. To further interrogate these findings, we triggered pathological remodeling using angiotensin II (Ang II). Phosphorylation of AMP-activated protein kinase (AMPK) signaling and histone deacetylase (HDAC) activity were found to be dependent on hormonal status and Ang II stimulation. Finally, knockdown of anti-inflammatory regulatory T cells (Treg) exacerbated Ang II-dependent fibrosis implicating HDAC-mediated epigenetic suppression of Treg activity. Taken together, we demonstrated unique cellular and molecular profiles underlying the cardiac phenotype of pre-, peri-, and menopausal mice supporting the necessity to study CVD in females across the hormonal transition.NEW & NOTEWORTHY Cycling and perimenopausal females are protected from cardiovascular disease (CVD) whereas menopausal females are more susceptible to CVD and other pathological sequalae. The cellular and molecular mechanisms underlying loss of CVD protection across the pre- to peri- to menopause transition remain understudied. Using the murine 4-vinylcyclohexene diepoxide (VCD) model of menopause we highlight cellular and molecular signatures from hearts at each hormonally distinct stage that included transcriptomic, proteomic, and cell biological analyses.

Sleep is an essential, tightly regulated biological function. Sleep is also a homeostatic process, with the need to sleep increasing as a function of being awake. Acute sleep deprivation (SD) increases sleep need, and subsequent recovery sleep (RS) discharges it. SD is known to alter brain gene expression in rodents, but it remains unclear which changes are linked to sleep homeostasis. To investigate this question, we analyzed RNA-seq data from adult male mice subjected to 3 and 5-6 h of SD and 2 and 6 h of subsequent RS. We hypothesized that molecular changes associated with sleep homeostasis would mirror sleep pressure dynamics as defined by brain electrical activity, peaking at 5-6 h of SD and no longer differentially expressed after 2 h of RS. We report that 5-6 h of SD produces the largest effect on gene expression, and the majority of differentially expressed genes normalize after 2 h of RS. These genes are involved in cellular redox homeostasis, DNA damage/repair, and chromatin regulation and may underlie the molecular basis of sleep homeostasis. Genes associated with cellular stress do not normalize within 6 h of RS and may underlie non-sleep-specific effects of SD. In addition, RS affects gene expression related to energy metabolism and Wnt-signaling, potentially contributing to its restorative effects. Finally, our study also points to the regulation of expression of a subset of circadian transcription factors as a function of sleep need. Overall, our results offer novel insights into the molecular mechanisms underlying sleep homeostasis and the broader effects of SD.NEW & NOTEWORTHY This study investigates different time points of sleep deprivation and recovery sleep to better understand the molecular processes influenced by sleep and lack of sleep. This study highlights redox metabolism, chromatin regulation, and DNA damage/repair as molecular mechanisms linked to sleep homeostasis while showing the effects of stress are probably non-sleep-specific based on transcriptional dynamics.

Neuromuscular electrical stimulation (NMES) can potentially be used to prevent venous thromboembolism; however, its impact on coagulation-related factors remains poorly understood. We aimed to investigate the acute effects on coagulation- and cardiovascular factors immediately after a 2-h NMES session. Levels of overall hemostatic potential (OHP), fibrinogen, factor VIII, and Olink proteomic cardiovascular factors were assessed before and after the NMES session in 36 healthy participants (20 males and 16 females) with a mean age of 31.9 yr. NMES was administered using integrated textile electrodes in pants (NMES pants). Mean intensities during the quadriceps, hamstrings, and gluteus muscle stimulation were 16.5, 20.5, and 25.4 mA, respectively, corresponding to submaximal intensity levels with acceptable discomfort (just below 4 on the visual analogue scale [VAS], 0-10). The NMES session resulted in a significant increase in mean (SD) OHP [94.4 (28.3) to 103 (31.0)], and overall coagulation potential [292 (50.4) to 307(49.8)], and a decrease in overall fibrinolytic potential [68.2 (5.46) to 67.1 (5.20)]. These changes were highly correlated with the increase in fibrinogen (all R > 0.7, P ≤ 0.001), but not with the increase in factor VIII. In addition, 18 of 92 cardiovascular proteins, specifically those involved in regulating inflammation and extracellular matrix remodeling, were influenced by NMES; however, low correlations were found between the changes in these proteins and OHP analyses. In conclusion, the NMES session resulted in a slight increase in the coagulative state, mirroring that seen after a bout of regular exercise. The changes observed in cardiovascular factors, which are mostly not directly related to coagulation, suggest that NMES may subsequently modulate inflammatory responses, warranting further investigation.NEW & NOTEWORTHY The immediate response to a 2-h neuromuscular electrical stimulation (NMES) session, delivered at an acceptable level of discomfort using NMES-pants, marginally increases the coagulative state, similar to what is observed after regular physical exercise. This change is not expected to significantly increase the risk of blood clotting, as all factors remain within the normal reference range. Interestingly, NMES simultaneously appears to affect proteins that regulate the transition of inflammation into an anti-inflammatory response.

Hyperosmolality is increasingly recognized as a factor contributing to severe COVID-19. Recently, a genetic variant near the aquaporin 3 (AQP3) water channel was associated with severe COVID-19 [rs60840586:G; odds ratio (OR): 1.07, P = 2.5 × 10^-9]. The variant is known to increase gene expression of AQP3 in several organs, including the lung [normalized expression scores (NES) = 0.33, P = 4.1 × 10^-20] in GTEx. In this study, we investigated 576 patients in the Biobanque Quebecoise de la COVID-19 (BQC-19) with both genetic and clinical data available. We estimated plasma osmolality using the formula: eOSM = 2 × [Na⁺] + 2 × [K⁺] + [Urea] + [Glucose]. Using a logistic regression of mortality against eOSM, genotype at rs60840586, sex, age, and the first 10 genetic principal components, we confirm that hyperosmolality is associated with COVID-19 mortality (OR = 2.06 [95% CI = 1.62-2.65], P = 9.13 × 10^-9). Interestingly, we found that the risk of death linked to hyperosmolality is influenced by the AQP3 variant rs60840586:G genotype (OR = 1.95 [95% CI = 1.22-3.28], P = 0.0075). However, the rs60840586 genotype did not independently affect mortality in this cohort. These findings suggest that the body's ability to regulate and accommodate hyperosmolality may be disrupted by overexpression of AQP3, potentially worsening outcomes in COVID-19. Given the role of AQP3 in water transport and homeostasis, further defining the functionality of its variants may provide key insights into COVID-19 severity and guide clinical management strategies, particularly in critically ill patients with hyperosmolality.NEW & NOTEWORTHY A genetic variant near water channel AQP3, linked to severe COVID-19, amplifies the risk of death in patients with elevated plasma osmolality. In patients hospitalized with COVID-19, we show that although the variant does not affect systemic osmolality directly, it interacts with hyperosmolality to increase mortality risk. These findings highlight a potential mechanism where AQP3 overexpression disrupts cellular water handling during critical illness, offering new insight into the role of water balance in COVID-19 pathophysiology.

Muscle disuse results in complex signaling alterations followed by structural and functional changes, such as atrophy, force decrease, and slow-to-fast fiber-type shift. Little is known about human skeletal muscle signaling alterations under long-term muscle disuse. In this study, we describe the effects of 21-day dry immersion on human postural soleus muscle. We performed both transcriptomic analysis and Western blots to describe the states of the key signaling pathways regulating soleus muscle fiber size, fiber type, and metabolism. Twenty-one-day dry immersion resulted in both slow-type and fast-type myofibers atrophy, downregulation of rRNA content, and mTOR signaling. Twenty-one-day dry immersion also leads to slow-to-fast fiber-type and gene expression shift, upregulation of p-eEF2, p-CaMKII, p-ACC content and downregulation of NFATc1 nuclear content. It also caused massive gene expression alterations associated with calcium signaling, cytoskeletal parameters, and downregulated mitochondrial signaling (including fusion, fission, and marker of mitochondrial density).NEW & NOTEWORTHY The main findings of our study are as follows: 1) The soleus slow fibers atrophy after 21-day dry immersion (DI) does not exceed that after 7-day DI; 2) The soleus ubiquitin ligases expression after 21-day DI returns to its initial level; 3) The soleus slow fibers atrophy after 21-day DI is accompanied by a mitochondrial apparatus structural markers decrease; 4) The soleus fibers signaling pathways restructuring process during 21-day DI is carried out in a complex manner.

The majority of exercise physiology research has been conducted in males, resulting in a skewed biological representation of how exercise impacts the physiological system. Extrapolating male-centric physiological findings to females is not universally appropriate and may even be detrimental. Thus, addressing this imbalance and taking into consideration sex as a biological variable is mandatory for optimization of precision exercise interventions and/or regimens. Our present analysis focused on establishing multiomic profiles in young, exercise-naïve males (n = 23) and females (n = 17) at rest and following acute exercise. Sex differences were characterized at baseline and following exercise using skeletal muscle and extracellular vesicle transcriptomics, whole blood methylomics, and serum metabolomics. Sex-by-time analysis of the acute exercise response revealed notable overlap, and divergent molecular responses between males and females. An exploratory comparison of two combined exercise regimens [high-intensity tactical training (HITT) and traditional (TRAD)] was then performed using singular value decomposition, revealing latent data structures that suggest a complex dose-by-sex interaction response to exercise. These findings lay the groundwork for an understanding of key differences in responses to acute exercise exposure between sexes. This may be leveraged in designing optimal training strategies, understanding common and divergent molecular interplay guiding exercise responses, and elucidating the role of sex hormones and/or other sex-specific attributes in responses to acute and chronic exercise.NEW & NOTEWORTHY This study examined methylomics, transcriptomics, and metabolomics in circulation and/or skeletal muscle of young, healthy, exercise-naïve males and females before and after exposure to either traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found an overlapping yet considerably sex-divergent response in the molecular mechanisms activated by exercise. These findings may provide insight into optimal training strategies for adaptation when considering sex as a biological variable.