Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA).

Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission-related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.

The Association of Skeletal Muscle Energetics With Recurrent Falls in Older Adults Within the Study of Muscle, Mobility and Aging.

BACKGROUND: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. METHODS: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax) after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. RESULTS: At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0 ± 0.2 vs 1.1 ± 0.2, p < .001), reported fewer alcoholic drinks per week in the past year (2.4 ± 4.3 vs 2.8 ± 4.4, p = .054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6 ± 4.4 vs 4.2 ± 3.4, p < .05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p = .008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p = .369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02-1.73, p = .033). However, covariates accounted for the increased risk. CONCLUSIONS: Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway.

Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers.

KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Because amino acid sequences of the three main RAS isoforms-KRAS, NRAS, and HRAS-are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. Although some inhibitors, like adagrasib, were highly selective for KRASG12C, others also potently inhibited NRASG12C and/or HRASG12C. Notably, sotorasib was five-fold more potent against NRASG12C compared with KRASG12C or HRASG12C. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors. SIGNIFICANCE: These studies demonstrate that certain KRASG12C inhibitors effectively target all RASG12C mutations and that sotorasib specifically is a potent NRASG12C inhibitor capable of driving clinical responses. These findings have important implications for the treatment of patients with NRASG12C or HRASG12C cancers and could guide design of NRAS or HRAS inhibitors. See related commentary by Seale and Misale, p. 698. This article is featured in Selected Articles from This Issue, p. 695.

Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations.

PIK3CA mutations occur in ∼8% of cancers, including ∼40% of HR-positive breast cancers, where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired resistance to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Kα inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K pathway, including PTEN loss and activating AKT1 mutations. Notably, although secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Kα inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kα-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kα-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers. SIGNIFICANCE: In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Kα inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Kα inhibitor. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 240 . This article is featured in Selected Articles from This Issue, p. 201.

Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging.

BACKGROUND: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). 31Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATPmax) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOSCI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders. RESULTS: One-SD decrements of most respirometry measures (e.g., Max OXPHOSCI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATPmax with frailty were weaker than those between Max OXPHOSCI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components. CONCLUSIONS: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the Study of Muscle, Mobility and Aging (SOMMA).

Autophagy is an essential component of proteostasis and a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy and mTOR/upstream pathways were determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400m walking speed, and leg power), and thigh muscle volume were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy and pexophagy (PPARGC1A, PPARA, EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion and fission related genes (NIPSNAP2, DNM1L, OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1) and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.

Muscle mass, strength, power and physical performance and their association with quality of life in older adults, the Study of Muscle, Mobility and Aging (SOMMA).

Background: Sarcopenia negatively impacts quality of life. It is unclear whether different measures of muscle size, strength, physical performance, and fitness have similar associations with quality of life. Objective: To describe associations of sarcopenia metrics with quality of life outcomes. Participants: Community-dwelling adults aged 70+ years participating in the SOMMA (Study of Muscle, Mobility and Aging) study. Design and settings: Two academic medical centers. Measurements: Measures included muscle size (MRI- muscle volume. D3Cr muscle mass); strength and power (grip strength, leg extension power and strength); walking and physical performance (4m and 400m walk, SPPB (Short Physical Performance Battery), stair climb, chair stand); fitness (VO2 peak); health related quality of life (EQ-5D); and anthropometrics (weight, height, and body mass index).Results were stratified by sex. Correlations, scatterplots and linear regression models described the association between various measures of sarcopenia and fitness with overall quality of life score (EQ5D VAS) as a continuous variable. We also quantified differences between sarcopenia and fitness measures by overall QOL (Quality of Life) as a categorical variable (low, medium, high) and by QOL subcomponents (pain and discomfort, problems with usual activities, mobility, anxiety and depression, and problems with self-care) using distributionally appropriate methods. Results: Walking tests and physical performance were most consistently (but modestly) associated with overall quality of life (r~0.2, p<.001) and its subcomponents. Both men and women several sarcopenia and fitness measures were more strongly associated with pain and usual activity than other QOL components. Conclusions: Poor performance, lower fitness and lower strength are related to worse quality of life, particularly pain, in older adults. Future studies should quantify these relationships longitudinally.

Higher Expression of Denervation-responsive Genes is Negatively Associated with Muscle Volume and Performance Traits in the Study of Muscle, Mobility and Aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8 th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO 2peak ), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calcium-dependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (Chrna1, Chrnd, Chrne), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO 2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervation-responsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

The association of skeletal muscle energetics with recurrent falls in older adults within the Study of Muscle, Mobility and Aging (SOMMA).

Background: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. Methods: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for recurrent falls (2+) after one year. Skeletal muscle energetics were assessed at baseline in vivo using 31 P Magnetic Resonance Spectroscopy (MRS) (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS). Results: SOMMA participants who reported recurrent falls (12%) had a slower 400m walk gait speed compared to those with 0-1 falls (1.0 +/-0.2 vs. 1.1 +/-0.2, p<.001) and took a greater number of medication in the 30 days before their baseline visit (5.6 +/-4.4 vs. 4.2 +/-3.4, p<0.05). MaxOXPHOS was significantly lower in those who reported recurrent falls (p=0.008) compared to those with one or fewer falls, but there was no significant difference in ATPmax (p=0.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (RR=1.33, 95% CI= 1.02-1.73, p=0.033). However, covariates accounted for the increased risk. Conclusions: Ex vivo maximal muscle mitochondrial energetics were lower in older adults who experienced recurrent falls, but covariates accounted for its association with recurrent fall risk, suggesting this "hallmark of aging" may not be directly implicated in the complex etiology of falls.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility and Aging (SOMMA).

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility and Aging. Expression levels of twenty-one protein coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including: maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.

The reciprocal relationship between cardiac baroreceptor sensitivity and cerebral autoregulation during simulated hemorrhage in humans.

A reciprocal relationship between the baroreflex and cerebral autoregulation (CA) has been demonstrated at rest and in response to acute hypotension. We hypothesized that the reciprocal relationship between cardiac baroreflex sensitivity (BRS) and CA would be maintained during sustained central hypovolemia induced by lower body negative pressure (LBNP), and that the strength of this relationship would be greater in subjects with higher tolerance to this stress. Healthy young adults (n = 51; 23F/28M) completed a LBNP protocol to presyncope. Subjects were classified as high tolerant (HT; completion of -60 mmHg LBNP stage, ≥20-min) or low tolerant (LT; did not complete -60 mmHg LBNP stage, <20-min). R-R intervals (RRI), systolic arterial pressure (SAP), mean arterial pressure (MAP), and middle cerebral artery velocity (MCAv) were measured continuously. Cardiac BRS was calculated in the time domain (ΔHR/ΔSAP) and frequency domain (RRI-SAP low frequency (LF) transfer function gain), and CA was calculated in the time domain (ΔMCAv/ΔMAP) and frequency domain (MAP-mean MCAv LF transfer function gain). There was a moderate relationship between cardiac BRS and CA for the group of 51 subjects in both the time (R = -0.54, P < 0.0001) and frequency (R = 0.61, P < 0.001) domains; there was a stronger relationship in the HT group (R = 0.73) compared to the LT group (R = 0.31) in the frequency domain (P = 0.08), but no difference between groups in the time domain (HT: R = -0.73 vs. LT: R = -0.63; P = 0.27). These findings suggest that an interaction between BRS and CA may be an important compensatory mechanism that contributes to tolerance to simulated hemorrhage in young healthy adults.

KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy.

Although KRAS has long been considered undruggable, direct KRASG12C inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear. We find that upstream feedback activation of wild-type RAS, as opposed to a shift in KRASG12C to its active guanosine triphosphate (GTP)-bound state, is sufficient to drive RAS-MAPK reactivation in a KRASG12C-independent manner. Moreover, multiple receptor tyrosine kinases (RTKs) can drive feedback reactivation, potentially necessitating targeting of convergent signaling nodes for more universal efficacy. Even in colorectal cancer, where feedback is thought to be primarily epidermal growth factor receptor (EGFR)-mediated, alternative RTKs drive pathway reactivation and limit efficacy, but convergent upstream or downstream signal blockade can enhance activity. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting KRAS.

Quantifying External Load and Injury Occurrence in Women's Collegiate Volleyball Players Across a Competitive Season.

ABSTRACT: Taylor, JB, Barnes, HC, Gombatto, SP, Greenwood, D, and Ford, KR. Quantifying external load and injury occurrence in women's collegiate volleyball players across a competitive season. J Strength Cond Res 36(3): 805-812, 2022-Volleyball demands repetitive jumping, with high loads linked to risk of injury. The purpose of this study was to examine jumping demands and injury patterns throughout a women's volleyball season. Sixteen Division-I female volleyball players wore an accelerometer to record jump count (JC) and jump height during every practice and match throughout the season. Physical health was documented using a weekly modified Oslo Sports Trauma Research Center Overuse Injury Questionnaire (OSLO) and time-loss injuries were recorded. Multivariate analyses of variance were used to compare measures across phases of the season, between types of session (practice vs. match), and between injured and noninjured players (α = 0.05). Results showed the greatest training demands in the preseason with larger jump counts than during the nonconference, conference schedule, and postseason schedules (p < 0.001). Performance increased throughout the season with greater jump heights in the nonconference and conference schedule than in the preseason (p = 0.01). There were no significant differences in JC between practices (65.5 ± 30.5) and matches (67.5 ± 46.4). An injury incidence of 5.49 injures per 1,000 athletic exposures was identified, with injuries accounting for 31 days lost, or 2.1% of total exposures. Injuries affected performance throughout the season, as noted by an average weekly OSLO score of 15.1 ± 13.9%. Injured players had significantly lower jump counts per exposure (p = 0.03) and a larger variation in training load than uninjured players (coefficient of variation: injured = 54%, uninjured = 41%; p = 0.006). These data help provide coaches and clinicians for training and rehabilitation program designs.

Peaks and valleys: oscillatory cerebral blood flow at high altitude protects cerebral tissue oxygenation.

Introduction.Oscillatory patterns in arterial pressure and blood flow (at ∼0.1 Hz) may protect tissue oxygenation during conditions of reduced cerebral perfusion and/or hypoxia. We hypothesized that inducing oscillations in arterial pressure and cerebral blood flow at 0.1 Hz would protect cerebral blood flow and cerebral tissue oxygen saturation during exposure to a combination of simulated hemorrhage and sustained hypobaric hypoxia.Methods.Eight healthy human subjects (4 male, 4 female; 30.1 ± 7.6 year) participated in two experiments at high altitude (White Mountain, California, USA; altitude, 3800 m) following rapid ascent and 5-7 d of acclimatization: (1) static lower body negative pressure (LBNP, control condition) was used to induce central hypovolemia by reducing chamber pressure to -60 mmHg for 10 min(0 Hz), and; (2) oscillatory LBNP where chamber pressure was reduced to -60 mmHg, then oscillated every 5 s between -30 mmHg and -90 mmHg for 10 min(0.1 Hz). Measurements included arterial pressure, internal carotid artery (ICA) blood flow, middle cerebral artery velocity (MCAv), and cerebral tissue oxygen saturation (ScO2).Results.Forced 0.1 Hz oscillations in mean arterial pressure and mean MCAv were accompanied by a protection of ScO2(0.1 Hz: -0.67% ± 1.0%; 0 Hz: -4.07% ± 2.0%;P = 0.01). However, the 0.1 Hz profile did not protect against reductions in ICA blood flow (0.1 Hz: -32.5% ± 4.5%; 0 Hz: -19.9% ± 8.9%;P = 0.24) or mean MCAv (0.1 Hz: -18.5% ± 3.4%; 0 Hz: -15.3% ± 5.4%;P = 0.16).Conclusions.Induced oscillatory arterial pressure and cerebral blood flow led to protection of ScO2during combined simulated hemorrhage and sustained hypoxia. This protection was not associated with the preservation of cerebral blood flow suggesting preservation of ScO2may be due to mechanisms occurring within the microvasculature.

The impact of acute central hypovolemia on cerebral hemodynamics: does sex matter?

Trauma-induced hemorrhage is a leading cause of disability and death due, in part, to impaired perfusion and oxygenation of the brain. It is unknown if cerebrovascular responses to blood loss are differentiated based on sex. We hypothesized that compared to males, females would have reduced tolerance to simulated hemorrhage induced by maximal lower body negative pressure (LBNP), and this would be associated with an earlier reduction in cerebral blood flow and cerebral oxygenation. Healthy young males (n = 29, 26 ± 4 yr) and females (n = 23, 27 ± 5 yr) completed a step-wise LBNP protocol to presyncope. Mean arterial pressure (MAP), stroke volume (SV), middle cerebral artery velocity (MCAv), end-tidal CO2 (etCO2), and cerebral oxygen saturation (ScO2) were measured continuously. Unexpectedly, tolerance to LBNP was similar between the sexes (males, 1,604 ± 68 s vs. females, 1,453 ± 78 s; P = 0.15). Accordingly, decreases (%Δ) in MAP, SV, MCAv, and ScO2 were similar between males and females throughout LBNP and at presyncope (P ≥ 0.20). Interestingly, although decreases in etCO2 were similar between the sexes throughout LBNP (P = 0.16), at presyncope, the %Δ etCO2 from baseline was greater in males compared to females (-30.8 ± 2.6% vs. -21.3 ± 3.0%; P = 0.02). Contrary to our hypothesis, sex does not influence tolerance, or the central or cerebral hemodynamic responses to simulated hemorrhage. However, the etCO2 responses at presyncope do suggest potential sex differences in cerebral vascular sensitivity to CO2 during central hypovolemia.NEW & NOTEWORTHY Tolerance and cerebral blood velocity responses to simulated hemorrhage (elicited by lower body negative pressure) were similar between male and female subjects. Interestingly, the change in etCO2 from baseline was greater in males compared to females at presyncope, suggesting potential sex differences in cerebral vascular sensitivity to CO2 during simulated hemorrhage. These findings may facilitate development of individualized therapeutic interventions to improve survival from hemorrhagic injuries in both men and women.

Jump load and landing patterns of collegiate female volleyball players during practice and competition.

BACKGROUND: Overuse lower extremity injuries are common in women's court volleyball players and are likely due to the repetitive jumping and landing the sport requires. The purpose of this study was to quantify jump load during collegiate women's volleyball, describe the quantity of double-leg (DL) to single-leg (SL) landing strategies, and compare loads and landing strategies between games and practices. METHODS: Fourteen collegiate Division-1 women's court volleyball players participated in the study. Volleyball-specific activity demands were quantified using video analysis from three consecutive practices and one match. Investigators recorded the total frequency of jump landings, and the frequency and percentage of double-leg (DL) landings and single-leg (SL) landings of fourteen collegiate Division-1 women's court volleyball players. Repeated measures ANOVAs identified differences in jumping load and percentages of DL and SL landings among practices and between practices and games (P<0.05). RESULTS: On average, there was a significantly higher overall jumping load (P=0.01) and frequency of DL (P=0.03) and SL (P=0.04) landings during practice than games, yet no differences between practices (P>0.05). Approximately 75% of all landings were DL, and individual patterns of DL to SL landings were consistent across events (P>0.05). CONCLUSIONS: Women's collegiate volleyball demands high volumes of repetitive jumping and landing with SL and DL support that may make these athletes susceptible to overuse injuries, especially during practice.