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Introduction: Severe menopausal hot flash symptoms are linked to the development of cardiovascular disease. Exaggerated blood pressure responses to exercise are also associated with an increased risk of hypertension and cardiovascular disease. It is unclear if females with more severe hot flash symptoms exhibit greater blood pressure responses to exercise compared to those with minimal menopausal hot flashes. We aimed to determine if there is a difference in the pressor response to isometric exercise between females with severe hot flash symptoms compared to females with no/low hot flash symptoms. We hypothesized that there will be exaggerated blood pressure responses to isometric handgrip exercise (IHG) and post-exercise ischemia (PEI) in females who have severe menopausal hot flashes compared to females with no/low hot flashes. Methods: We studied 19 female participants (age: 51±5yrs) with no history of cardiovascular disease or hypertension. The Menopausal Rating Scale (MRS) was used to assess the hot flash symptom severity and to group the participants into no/low (no-or-mild on MRS) or high (moderate-or-severe on MRS) hot flash symptom groups. Continuous blood pressure (BP) was measured via photoplethysmography and calibrated relative to a brachial arm cuff pressure. After 2 minutes of quiet rest, participants performed 2 minutes of IHG at 30% of maximal voluntary contraction, followed by 2 minutes of PEI on the exercising arm to isolate the metaboreflex. The severity groups were compared via independent samples t-tests. Results: There were 13 females in the no/low group and 6 females in the high group. Baseline heart rate (HR, no/low: 60±11 vs high: 58±8bpm), systolic (SBP, no/low:129±18 vs high: 120±14mmHg), diastolic (DBP, no/low: 72±12 vs high: 63±7mmHg) and mean BP (MBP, no/low: 91±11 vs high 82±9mmHg) were not different between groups. There were no differences in the pressor responses to IHG between groups (HR: no/low: Δ6±5 vs high: 5±4bpm, p=0.425; SBP: no/low: Δ9±5 vs high: 11±6mmHg, p=0.408; DBP: no/low: Δ5±3 vs high: 7±4mmHg, p=0.182; MBP: no/low: Δ6±3 vs high: 8±4mmHg, p=0.253). There was also no difference in the pressor response to PEI between groups (HR: no/low: Δ6±6 vs high: 4±2bpm, p=0.554; SBP: no/low: Δ11±6 vs high: 16±9mmHg, p=0.191; DBP: no/low: Δ5±3 vs high: 8±6mmHg, p=0.298; MBP: no/low: Δ7±4 vs high: 11±7mmHg, p=0.280). Conclusion: The current data show no differences in the blood pressure responses to IHG or PEI between females with different menopausal hot flash symptom severities. This suggests that pressor responses to an IHG exercise and the metaboreflex may not be notable contributors to the increased cardiovascular risk in females with severe menopausal hot flashes. NIH: K01 HL148144, NCATS UL1 TR000135, UL1 TR002377; AHA: 898649. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Menopausal females who experience frequent hot flashes (episodes of increased body temperature and sweating) have a greater risk of hypertension and cardiovascular disease than females without hot flashes. Individuals with exaggerated blood pressure (BP) responses to cold stress have a higher risk of hypertension than those with lower responses. It is unknown if females who experience hot flashes have exaggerated pressor responses to cold stress, indicating their greater risk of hypertension. The aim of this study was to determine the pressor responses to cold stress in females who experience hot flashes and those who do not. An additional goal was to understand the relation between daily hot flash frequency and pressor responses. We hypothesized that females with hot flashes would have exaggerated pressor responses to cold stress compared to females without hot flashes. We also hypothesized that pressor responses would be positively correlated to daily hot flash frequency. We recruited 17 females, ages 45-60 years, without hypertension or cardiovascular disease, who did and did not have hot flashes. They reported hot flash frequency in a 3-day written diary. On the study day, continuous BP (finger photoplethysmography, calibrated to brachial cuff BP) and heart rate (HR; 3-lead ECG) were recorded while the participant rested during a 2-minute baseline period, then subsequently had an ice-water pack placed on their forehead for 3 minutes. The changes in mean BP (MBP) and HR are calculated as the change in MBP or HR during the cold pressor test minus the average MBP or HR during baseline. Data were analyzed using the Student’s t-test and Pearson correlation. Twelve females reported hot flashes (age: 51±4 years; average number of hot flashes: 3 per day) and five did not (age: 49±5 years). These groups did not differ in age, body mass index, resting MBP, or resting HR (p>0.05 for all). The change in MBP from baseline to the cold pressor test did not differ between females with and without hot flashes (Δ17±10 vs. Δ19±14 mmHg, respectively; p=0.860). The change in HR with the cold pressor test also did not differ between females who did and did not report hot flashes (Δ10±6 vs. Δ12±8 mmHg, respectively; p=0.647). In females with hot flashes, the number of hot flashes reported per day (range: 1-12 per day) was not correlated with the change in MBP (p=0.824) or HR (p=0.460) during the cold pressor test. These current data show that menopausal females who experience hot flashes do not exhibit exaggerated BP or HR responses to cold stress in comparison to females who do not experience hot flashes. In addition, BP and HR responses are not correlated with daily hot flash frequency. There are likely other vascular mechanisms that place menopausal females with hot flashes at an increased risk for hypertension. In addition, incorporating information on the age at which hot flashes began, as well as hot flash severity, might help us to further understand cardiovascular risk in this population. AHA 898649, NIH T32 DK07352, K01 HL148144, NCATS UL1 TR002377. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Patients with obstructive sleep apnea (OSA) have increased risk for cardiovascular diseases. Data from the Atherosclerosis Risk in the Communities and Sleep Heart Health Study suggest that OSA is more deleterious to females versus males, although mechanistic data are lacking. Estimates of central (aortic) blood pressure (BP) are superior in predicting future cardiovascular events than traditional brachial BP measurements. While patients with OSA have altered central hemodynamics (e.g., higher aortic pulse wave velocity; PWV), potential sex differences are unexplored. We tested the hypothesis that females with OSA (n=7, 50±3yrs, 35.1±1.9kg/m2, 22.2±7.6 events/hr) have worse central hemodynamics than males with OSA (n=9, 47±3yrs, 35.0±1.4kg/m2, 31.7±6.2 events/hr). Data collection consisted of an overnight sleep study (polysomnography) to identify the presence, and characterize the severity, of OSA via the apnea-hypopnea index (AHI). Then, duplicate measures of central (aortic) and peripheral (brachial) BP, as well as central artery stiffness (PWV) and wave reflection (AIx), were made in the morning after ≥15min of quiet, supine rest. Additional hemodynamic measurements were made if data differed by ≥2% (AIx) or ≥0.5m/s (PWV). Data that met these criteria were averaged and used for analysis. Comparisons were made using two-tailed, independent samples t-tests or nonparametric Mann-Whitney Rank Sum tests, as indicated. No differences were observed in age (p=0.44), body mass index (p=0.96), nor AHI (p=1.00) between sexes. Similarly, no sex differences were observed in brachial systolic (female vs. male: 129±7 vs. 134±8mmHg, p=0.83), diastolic (77±5 vs. 85±4mmHg, p=0.26), or mean BP (96±6 vs. 101±5mmHg, p=0.45). Similarly, central systolic (122±6 vs. 125±7mmHg, p=0.96), diastolic (78±5 vs. 86±4mmHg, p=0.25), and augmentation (21±2 vs. 15±2mmHg, p=0.07) BP did not differ between sexes. Resting heart rate was also comparable between groups (67±3 vs. 65±2bpm, p=0.64). However, AIx (AIx; 42±3 vs. 35±4%) and AIx normalized to a heart rate of 75bpm (42±3 vs. 30±3%) were higher in females with OSA relative to males with OSA (p<0.05 for both). Interestingly, the forward (30±3 vs. 28±2mmHg, p=0.63) and reflected (20±2 vs. 18±2mmHg, p=0.44) pulse heights, as well as PWV (7.3±0.6 vs. 7.4±0.6m/s, p=0.85), were similar between groups. Our data indicate that despite a trend towards higher BP in males with OSA (~5mmHg) that may be clinically, though not statistically different, females with OSA have a higher AIx. As AIx is positively associated with left ventricular hypertrophy, these data also suggest that altered central (aortic) hemodynamics may contribute to the sex differences in cardiovascular risk with OSA. This work was supported by the National Institutes of Health T32-HL007111 and U54AG044170 (JMB), HL065176 (PS and VKS), and HL134885 (VKS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Cystic fibrosis (CF) is a genetic disorder in which patients have dysfunctional cystic fibrosis transmembrane regulatory (CFTR) proteins in the lungs that disrupt ion regulation resulting in a thick, viscous mucus layer on the airway epithelium. Consequential poor mucociliary clearance leads to repeated infections and chronic inflammation contributing to bronchiectasis which is associated with increased airway luminal area. CFTR modulator therapy can improve and even restore the function and expression of a mutated CFTR gene which has been shown to improve sweat chloride levels and pulmonary symptoms rapidly. However, the effect of CFTR modulator therapy on large conducting airway luminal area is unclear. We compared large conducting airway luminal area in patients with CF before and after initiating CFTR modulator therapy. We hypothesized that airway luminal area would normalize (decrease) after initiating CFTR modulator therapy. Methods: Twenty-three patients with CF (32±15 years, 11 female) with computed tomography (CT) imaging of their lungs before and after initiating CFTR modulator therapy were included in analyses. In each patient we measured seven large conducting airways (trachea, left and right main bronchus, bronchus intermediate, left and right upper lobe, and left lower lobe) before and after CFTR modulator therapy initiation. To control the potential effect of height, airway luminal area (mm2) was divided by patient height (cm). Paired t-tests compared differences between luminal area before after initiating CFTR modulator therapy. Results: Patients were taking CFTR modulator therapy for a median of 1.1 years (range: 22–2111 days) at the time of their CT imaging after initiating CFTR modulator therapy. Large conducting airway luminal area was not different before and after initiating CFTR modulator therapy in all seven airways: trachea (1.50±0.35 vs. 1.56±0.34 mm2/cm, p=0.14), right main bronchus (1.05±0.21 vs. 1.09±0.19 mm2/cm, p=0.11), bronchus intermediate (0.68±0.16 vs. 0.68±0.16 mm2/cm, p=0.54), right upper lobe (0.42±0.10 vs. 0.45±0.09 mm2/cm, p=0.27), left main bronchus (0.81±0.19 vs. 0.83±0.18 mm2/cm, p=0.21), left upper lobe (0.51±0.13 vs. 0.52±0.13 mm2/cm, p=0.45), and left lower lobe (0.44±0.11 vs. 0.46±0.10 mm2/cm, p=0.42). Conclusion: There was no change in large conducting airway luminal area after initiating CFTR modulator therapy suggesting CFTR modulator therapy may not reverse CF-associated airway luminal area changes. However, longitudinal analysis and investigation into the small airways are necessary for a comprehensive understanding of the effect of CFTR modulator therapy on airway luminal area changes. Funding: NIH (HL139854 to MJJ, HL131151 to SEB) and NSERC (PDF-577750-2023 to AHR). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome or sudden cardiac death due to a separation of arterial wall layers. The majority of patients with SCAD are females (>80%) with few to no traditional cardiovascular risk factors. Though the physiological mechanisms that predispose to SCAD are unknown, common triggers for SCAD events include sympathoexcitatory stimuli, such as mental and emotional stress. Additionally, studies report high prevalence of depression and anxiety among patients with SCAD. Our study aimed to investigate cardiovascular responses to mental stress in patients with SCAD. We hypothesized that patients with SCAD would have exaggerated cardiovascular responses to mental stress compared to healthy controls. Methods: Four female patients with SCAD were age-, and BMI-matched with 4 healthy females. Participants underwent 2 minutes of baseline quiet rest, a 5-minute Stroop Color Word Test to induce mental stress, followed by 2 minutes of recovery. Continuous beat-to-beat blood pressure (BP, finger photoplethysmography) and heart rate (HR, 3-lead ECG) were recorded. Venous occlusion plethysmography was used to measure forearm blood flow (FBF). Forearm vascular conductance (FVC) was calculated as FBF/mean BP×100. Data are presented as change from baseline (Δmean±SD). Group data were compared using independent samples t-tests. Results: Resting hemodynamic parameters (Systolic [SBP], Diastolic [DBP], and Mean BP [MBP], Pulse pressure [PP], and HR) and FVC were similar between groups. Patients with SCAD had greater increases in DBP (Δ12±5 vs. Δ1±5 mmHg, p=0.02) and PP (Δ5±3 vs. Δ-7±8 mmHg, p=0.04) during the last minute of mental stress test compared to controls. Although, there were no differences in the changes of SBP (Δ17±7 vs. Δ-1±13 mmHg, p=0.05), MBP (Δ13±6 vs. Δ3±8 mmHg, p=0.08), HR (Δ8±0 vs. Δ10±2 bpm, p=0.12), or FVC (Δ1.5±1.2 vs. Δ1.8±1.3 ml/min/100 mmHg, p=0.80) between groups. During the last minute of recovery, there were no differences in hemodynamic parameters (SBP: Δ6±9 vs. Δ-4±10 mmHg, p=0.23; DBP: Δ2±7 vs. Δ-3±2 mmHg, p=0.22; MBP: Δ3±7 vs. Δ-3±5 mmHg, p=0.22; PP: Δ4±5 vs. Δ-1±8 mmHg, p= 0.35; HR: Δ-1±3 vs. Δ0±3 bpm, p=0.64), or FVC (Δ1.3±1.7 vs. Δ0.5±0.3 ml/min/100 mmHg, p= 0.35) between groups. Conclusion: These preliminary data suggest that patients with SCAD have greater increases in DBP and PP in response to mental stress compared to healthy controls. These exaggerated pressor responses might have implications for the pathophysiology of SCAD. NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome via the sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is >80% female who typically have few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Risk of a recurrent SCAD is reported as high as 19% at 3 years after an initial SCAD. Mechanisms underlying SCAD (re)occurrence are unknown. Common triggers for SCAD include sympathoexcitatory stimuli, including heavy exercise and intense Valsalva-like activities. This study tested the hypothesis that SCAD patients exhibit greater neurocardiovascular responses (e.g., blood pressure, heart rate, muscle sympathetic nerve activity) to isometric handgrip and post-exercise ischemia compared to healthy females. Methods: Eight females with a history of SCAD (age: 56±6 yrs, BMI: 28±4 kg/m2) and 6 age- and BMI-matched healthy female controls (CON, age: 55±8 yrs, BMI: 26±5 kg/m2) participated. Continuous blood pressure (finger photoplethysmography) and heart rate (3-lead ECG) were measured during rest (1 minute), isometric handgrip at 30% maximal voluntary contraction (2 minutes), and post-exercise ischemia at 220 mmHg (2 minutes) to isolate the skeletal muscle metaboreflex. Muscle sympathetic nerve activity (MSNA, peroneal microneurography) was measured in a subset of participants (5 SCAD/4 CON). Data are presented as an absolute change from rest (mean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (SCAD: 96±8 vs CON: 91±9 mmHg, p=0.354), heart rate (SCAD: 56±11 vs CON: 59±10 bpm, p=0.666), and MSNA (SCAD: 50±19 vs CON: 43±32 bursts/100 heartbeats, p=0.697) were not different between groups. Relative to healthy controls, SCAD patients elicited greater increases in mean blood pressure during isometric handgrip (SCAD: Δ9±3 vs CON: Δ4±4 mmHg, p=0.034) and post-exercise ischemia (SCAD: Δ7±4 vs CON: Δ3±3 mmHg, p=0.046). There were no group differences regarding heart rate responses during isometric handgrip (SCAD: Δ3±4 vs CON: Δ4±4 bpm, p=0.359) and post-exercise ischemia (SCAD: Δ3±4 vs CON: Δ2±3 bpm, p=0.861). Responses in MSNA during isometric handgrip (SCAD: Δ12±8 vs CON: Δ9±8 bursts/100 heartbeats, p=0.536) and post-exercise ischemia (SCAD: Δ11±2 vs CON: Δ13±10 bursts/100 heartbeats, p=0.713) also were not different between groups. Conclusion: These preliminary data suggest that compared to healthy females, female patients who experienced a SCAD exhibit greater pressor, but not chronotropic or sympathetic, responses to isometric handgrip and post-exercise ischemia. Exaggerated pressor responses to these perturbations may be a potential risk factor for SCAD (re)occurrence. NIH K23 HL155506, NIH T32 DK07352, NIH K01 HL148144, NIH UL1 TR0022377, and AHA 898649. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chloroquine is an antimalarial agent commonly used as an autophagy inhibitor by preventing autolysosomal fusion. Autophagy is an important cellular process through which defective cytoplasmic structures are recycled and degraded that has been implicated in aging neuromuscular effects. We recently showed that acute chloroquine treatment blunts the maximal forces generated by the diaphragm muscle, likely by impairing neuromuscular transmission generally consistent with aging effects in the diaphragm muscle. In addition, old mice show increased accumulation of autophagy proteins in phrenic motor neurons, consistent with impaired autophagy flux. In the present study, we hypothesized that chloroquine treatment results in accumulation of bulk endosomes pre-synaptically. Each hemidiaphragm with attached phrenic nerve was excised from 24-month-old male and female C57BL/6 mice to evaluate frequency dependent (0 vs 80 Hz stimulation) uptake of the styryl dye FM4-64, given that 80-Hz stimulation frequency induces bulk endocytosis after synaptic vesicle retrieval. Diaphragm-phrenic nerve preparations were incubated in 5 μM FM4-64 for 1 h prior to 6-min nerve stimulation (0.5 ms supramaximal pulses in 80 Hz, 200 ms trains delivered at 40% duty cycle) followed by a 5-min post-stimulation incubation. FM4-64 uptake at diaphragm neuromuscular junctions (NMJs) was measured using confocal microscopy. Preparations were randomly assigned to co-incubation with chloroquine (50 μM) or vehicle (Rees-Simpson solution). There was minimal FM4-64 uptake in the absence of phrenic nerve stimulation, consistent with the activity-dependent uptake of the styryl dye. With 80 Hz stimulation, high levels of FM4-64 uptake were evident in both the chloroquine and vehicle-treated groups without significant differences across groups. FM4-64 fluorescence was evident throughout the presynpatic terminal with few areas of dense accumulation, consistent with retention of endosomes. There was no evidence of greater endosome accumulation with chloroquine treatment. Of note, a slight increase in FM4-64 uptake was evident in the chloroquine treated groups compared to vehicle in the non-stimulated NMJs. These results are consistent with FM4-64 uptake reflecting bulk endocytosis that mainly occurs during high frequency stimulation. The impairment in autophagy flux following chloroquine treatment is expected to result in endosome accumulation but it is possible that the stimulation protocol was insuffcient to elucidate this possibility. Collectively, the findings of this study are consistent with impaired autophagy at diaphragm presynaptic terminals which may underlie neuromuscular deficits observed in old age. Supported by NIH grant R01 AG057052 and the Mayo Clinic. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chloroquine (CQ), an antimalarial agent, inhibits autophagy by preventing the autophagosome from fusing with the lysosome, emulating the effects of aging. Autophagy is a cellular digestion process that contributes to homeostasis through degradation of cytoplasmic structures in the cell. Aging effects include autophagy impairment, leading to the accumulation of altered proteins and organelles, thus contributing to subsequent cell damage and death. Previous studies in phrenic motor neurons show an age-dependent increase in key autophagy proteins LC3 and p62, reflecting autophagy impairment and autophagosome accumulation. In addition, acute chloroquine administration in old mice decreases maximal transdiaphragmatic pressure generation, suggesting a neuromuscular effect in aging. We hypothesized that treatment with the autophagy inhibitor chloroquine alters pre-synaptic morphology and increases the proportion of denervated diaphragm muscle fibers. Adult male and female 6-month C57BL6 mice were used to examine diaphragm muscle neuromuscular junction (NMJ) morphology and denervation. The autophagy inhibitor chloroquine (10 mg/kg/d) or vehicle was administered via daily intraperitoneal injections for 7 days. Confocal microscopy was used to compare pre- and post-synaptic morphology and denervation. There was evidence of a decrease in pre-synaptic volume without evidence of post-synaptic volume changes in chloroquine treated mice compared to vehicle. As expected, vehicle treated mice did not show evidence of substantial denervation. In contrast, chloroquine treated mice showed an increased proportion of denervated NMJs. The morphological changes observed were similar to those previously reported in the diaphragm muscles of 24-month-old mice. These findings reveal the effects at the neuromuscular junction of inhibiting autophagy and implicate impaired autophagy as a mechanism of aging effects. Supported by NIH R01 AG057052 and Mayo Clinic. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Females who experience menopausal hot flashes ([MHF]; episodes of sudden warmth and sweating) have greater risk of developing hypertension than females without MHF. MHF symptom severity and frequency are positively associated with hypertension. Considering that augmented arterial stiffness contributes to hypertension, this work aimed to investigate the relations between MHF severity and frequency with arterial stiffness. We hypothesized that females with moderate to severe MHF symptoms would exhibit greater arterial stiffness compared to females without MHF symptoms. Further, we hypothesized that there would be a positive relation between MHF frequency and arterial stiffness. Methods: Twenty-five females (51±5 [SD] years) with no history of hypertension or cardiovascular disease participated. The Menopausal Rating Scale was used to categorize participants by symptom severity (None MHF: n=7, Mild MHF: n=9, Moderate/Severe MHF: n=9). Participants self-reported MHF frequency over three consecutive days in real time using a hot flash diary (4±5 MHF/day, Range: 0-16). After 15 minutes of supine rest, brachial cuff blood pressures (sphygmomanometer) and heart rate (electrocardiogram) were recorded. Arterial stiffness was measured as pulse wave velocity ([PWV]; SphygmoCor®). PWV was measured using a carotid tonometer simultaneously with a leg cuff to capture blood pressure waveforms at the carotid and femoral sites. Aortic systolic pressure, aortic diastolic pressure, and augmentation index (AIx) were measured via pulse wave analysis ([PWA]; SphygmoCor®) using a brachial cuff. Data were analyzed using one-way analysis of variance (ANOVA) and Spearman Rho (ρ). Results: Age, body mass index, resting mean blood pressure, and resting heart rate were not different among MHF severity groups (P>0.05 for all). PWV was not different among severity groups (None: 6.2±0.67 vs. Mild: 6.4±1.0 vs. Moderate/Severe: 6.6±1.0 cm/s, P=0.72). MHF frequency did not correlate with PWV (P=0.42). Aortic systolic pressure (None: 110±6 vs. Mild: 114±5 vs. Moderate/Severe: 112±11 mmHg, P=0.66), aortic diastolic pressure (None: 76±9 vs. Mild: 77±6 vs. Moderate/Severe: 76±10 mmHg, P=0.93), and AIx (None: 31.9±9.0 vs. Mild: 38.7±11.1 vs. Moderate/Severe: 30.4±7.4 %, P=0.16) were not different among severity groups. MHF frequency did not correlate with metrics of PWA (Systolic: P=0.61; Diastolic: P=0.89, AIx: P=0.42). Conclusion: Arterial stiffness and metrics of PWA were not different among females with varying MHF symptom severity. MHF frequency was also not correlated with aortic stiffness and metrics of PWA. Other mechanisms of vascular function (e.g., autonomic function, vasodilation, and/or vasoconstriction) should be investigated to determine potential contributors of hypertension risk in females with MHF. AHA 898649, NIH T32 DK07352, K01 HL148144, NCATS UL1 TR002377. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Skeletal muscle is a highly plastic tissue, adapting its structure and metabolism in response to various stimuli like exercise. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to an acute exercise bout in volunteers with a range of insulin sensitivities. We studied 14 sedentary participants (7 male/7 female): age = 34.5 ± 3.1 years, body mass index = 29.3 ± 1.9 kg/m2 and HbA1c = 5.3 ± 0.1 %. We performed VO2peak tests to determine exercise capacity (VO2peak = 25.5 ± 1.6 mL per Kg per minute) and euglycemic hyperinsulinemic clamps (Rd value = 5.9 ± 0.8 mg per Kg per minute) with vastus lateralis muscle biopsies before and 30 minutes after a single 48-minute exercise bout. We extracted DNA from the muscle biopsies and performed reduced representation bisulfite sequencing. After performing quality control on the sequencing data, 1,034,947 sites were included for downstream analyses. MethylSig analysis revealed 17,030 differentially methylated cytosines (DMC), 9,020 increased and 8,010 decreased. To identify biologically meaningful DMCs, we used a mean change of >10%, which resulted in 1,179 and 1,436 increased and decreased sites, respectively. Pathway analysis of the increased DMCs revealed an enrichment in efferocytosis, leukocyte transendothelial migration, and FOXO-mediated transcription of oxidative stress pathways. In addition, pathway analysis of the decreased DMCs revealed an enrichment in metabolic (type 2 diabetes/ PI3K-Akt signaling), actin cytoskeleton, integrin/extracellular matrix and calcium signaling pathways. Our study reveals that an acute exercise bout induces alterations in the DNA methylation of skeletal muscle, impacting specific pathways in individuals with varying degrees of insulin sensitivity. Notably, our findings underscore the remarkable plasticity of skeletal muscle tissue. This research was funded by the National Institutes of Health, grant number R01DK094013 (Dawn Coletta). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.