Abstract Cardiovascular disease (CVD) is the leading cause of death in aging women. While CVD etiology is multifactorial, mitochondrial dysfunction, characterized by reduced content, impaired energy production, and increased oxidative stress, is an underlying contributor. These impairments reduce the ability of the heart and vasculature to support peripheral tissues. Estradiol, a key sex hormone with widespread physiological effects, supports mitochondrial function, lipid oxidation, vascular endothelial cell and smooth muscle function, and redox balance, contributing to its cardioprotective effects in women. Perimenopause is marked by hormonal variability and an overall decline in estradiol concentrations that may compromise mitochondrial quality and vascular function, increasing CVD risk. Mitochondrial quality and maintenance are largely controlled by the peroxisome proliferator‐activated receptor gamma coactivator‐1 (PGC‐1) family of transcriptional coactivators. Impairments in PGC‐1 isoform expression have been linked to cardiovascular and metabolic decline and may be exacerbated by estradiol loss during the menopause transition. However, the mechanisms by which estradiol signaling regulates PGC‐1 isoforms, and how this interaction contributes to mitochondrial dysfunction and CVD development following menopause, have not been comprehensively described. Thus, this review aims to highlight current evidence on the individual and overlapping roles of estradiol and PGC‐1 isoforms and examine how their interaction may contribute to the development of CVD following menopause.
Abstract Approximately 95% of Alzheimer's disease (AD) diagnoses are sporadic onset, present after the age of 65, and arising from a combination of non‐modifiable and modifiable factors. This underscores the potential to identify early systemic changes that may contribute to disease development. One factor may be skeletal muscle atrophy, which has been associated with cognitive decline, although the exact relationship between skeletal muscle and the brain is unknown. Furthermore, whether muscle atrophy begins prior to or after the onset of AD remains elusive. The humanized amyloid‐beta knock‐in mouse (hAβ‐KI) exhibits age‐related cognitive decline, insoluble Aβ accumulation, inflammation and microglial activation, making it a useful model of sporadic AD. However, characterization of skeletal muscle changes with aging has yet to be examined. Here, we assess skeletal muscle form and function of the hAβ‐KI mouse at 8 and 15 months of age, before and after onset of cognitive decline, through assessment of whole‐body lean mass percentage, isolated muscle contraction of the extensor digitorum longus (EDL) and soleus muscle, and fiber type analysis of male and female mice. Whole‐body lean mass declined over time in all mice; however, only male hAβ‐KI mice had a significant change in body mass and lean mass over the study. At 8‐months‐old, the isolated EDL of male hAβ‐KI mice fatigued faster than the WT mice, but there were no differences at 15 months‐old nor fiber type composition at either age. Alternatively, the isolated EDL and soleus of 8‐month‐old hAβ‐KI female mice fatigued slower compared to the WT mice, and there were no differences at 15 months nor fiber type composition at either age. This preliminary characterization work suggests sex‐dependent differences in isolated muscle fatigue prior to cognitive decline in the hAβ‐KI mouse model of sporadic AD.
Abstract This study evaluated the off‐the‐shelf predictive accuracy of four original W′‐balance recovery models (Morton and Billat linear, W′ BAL‐INT , W′ BAL‐ODE and W′ BAL‐CAEN ) and proposed a single‐coefficient modified linear formulation (Linear _mod ) for predicting high‐intensity interval training (HIIT) performance with passive recovery in trained runners. Twenty‐seven trained runners completed a 9/3‐min running critical power (CP) test and two open‐ended HIIT sessions to volitional exhaustion at 108% CP with a 2:1 work: rest ratio. Work intervals were individualized so that energy expenditure above CP equalled 40% (HIIT40%) or 60% (HIIT60%) of W′. The original models were applied using their published parameters. All substantially over‐predicted the number of intervals completed (pooled MAE 26.4–72.4 intervals; bias +20.1 to +72.4). Linear _mod with its default recovery coefficient ( R = 1) achieved a MAE of 4.85 intervals. Optimizing R at the population level ( R = 1.63) reduced MAE to 2.85 intervals, while athlete‐specific optimisation ( R = 1.54 ± 0.29) reduced MAE to 0.55 intervals. Individual R values were stable between protocols (within‐subject CV = 9.9%). Original W′‐balance models did not accurately predict running HIIT performance, whereas Linear _mod provided high predictive accuracy using a single athlete‐specific recovery coefficient.
Abstract Although stress can stimulate the vagus nerve via the brain–gut axis to induce enterohormone secretion from enteroendocrine cells (EECs), little is currently known about the roles of ion channels in the regulation of enterohormone secretion and the development of irritable bowel syndrome (IBS). We aimed to investigate whether transient receptor potential vanilloid 4 (TRPV4) channels and Na + /Ca 2+ exchanger 1 (NCX1) are critical for enterohormone secretion and whether they are involved in IBS. Ca 2+ imaging and patch‐clamp were applied to STC‐1. IBS‐diarrhea (IBS‐D) mouse model was established by wrap restraint stress (WRS). Western blot verified TRPV4 and NCX1 expressions in STC‐1; co‐immunoprecipitation demonstrated their physical interaction, and Ca 2+ imaging and patch‐clamp confirmed function and interaction. Carbachol (CCh), a stable analog of acetylcholine (ACh), induced Ca 2+ signaling and currents in EECs via a functional coupling of TRPV4 and NCX1. Moreover, intestinal cholecystokinin (CCK) transcripts in IBS‐D mice were significantly increased, and ACh enhanced intestinal CCK secretion in mice, all of which could be abolished by blockers of TRPV4, NCX1, and CCK receptors. Finally, these blockers alleviated the severity of IBS‐D in mice. We reveal a novel TRPV4/NCX1/Ca 2+ /CCK pathway in EECs, which is involved in the pathogenesis of IBS‐D. Targeting this pathway may hold promise for the prevention/treatment of IBS‐D.
Abstract The long noncoding RNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is a master regulator of transcriptional and posttranscriptional changes in stress responses. Here we assessed Neat1 lncRNA expression using quantitative PCR in peripheral biological fluids (saliva and blood) and a brain region that regulates stress and emotion (ventromedial hypothalamus) of 12‐week‐old pigs exposed to chronic (social mixing causing conflict) and acute (restraint) psychosocial challenges. We demonstrated that Neat1 is measurable in pig saliva, blood, and brain samples. Successful Neat1 lncRNA measurements in all three tissue types further established both broad tissue expression as well as the cross‐species conserved sequence of the NEAT1 gene. We found that Neat1_2 and Neat1 total expression did not correlate between tissues, suggesting variable expression throughout the body, and no significant differences in Neat1 lncRNA levels with either stressor. We also observed across all treatment groups changes in Neat1_2 and cortisol levels comparing samples taken before the intervention, compared to after, indicating confounding factors may have impacted the model. Overall, this study demonstrates the feasibility of measuring Neat1 in biological fluids obtained from farm mammals, with further work required to assess Neat1 lncRNA as a molecule involved in the physiological response to psychosocial stress.
