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Peripheral artery disease (PAD) is an atherosclerotic condition that impairs blood flow to the lower extremities, resulting in myopathy in affected skeletal muscles. Improving our understanding of PAD and developing novel treatment strategies necessitates a comprehensive examination of cellular structural alterations that occur in the muscles with disease progression. Here we aimed to employ electron microscopy to quantify skeletal muscle ultrastructural alterations responsible for the myopathy of PAD. Fifty-two participants (22 controls, 10 PAD Stage II, and 20 PAD Stage IV) were enrolled. Gastrocnemius biopsies were obtained to determine mitochondrial respiration and oxidative stress. Skeletal muscle sarcomere, mitochondria, lipid droplets, and sarcoplasm were assessed using transmission electron microscopy and focused ion beam scanning electron microscopy. Controls and PAD Stage II patients underwent walking performance tests: 6-minute walking test, 4-minute walking velocity, and maximum graded treadmill test. We identified several prominent ultrastructural modifications in PAD gastrocnemius, including reduced sarcomere dimensions, alterations in mitochondria number and localization, myofibrillar disorientation, changes in lipid droplets, and modifications in mitochondria-lipid droplet contact area. These changes correlated with impaired mitochondrial respiration and increased ROS production. We observed progressive deterioration in mitochondrial parameters across PAD stages. Stage II PAD showed impaired mitochondrial function and structure, while stage IV exhibited further deterioration, more pronounced structural alterations, and a decrease in mitochondrial content. The walking performance of Stage II PAD patients was significantly reduced. Our findings suggest that pathological mitochondria play a key role in the skeletal muscle dysfunction of PAD patients and represent an important target for therapeutic interventions aimed at improving clinical and functional outcomes in this patient population. Our data indicate that treatments should be implemented early and may include therapies designed to preserve and enhance mitochondrial biogenesis and respiration, optimize mitochondrial-lipid droplet interactions, or mitigate oxidative stress.

Abstract Transcranial direct current stimulation (tDCS) has been used extensively but research on its efficacy within the sport and exercise science realm has been inconsistent. There may be placebo and nocebo effects present with its use. Our objective was to determine if subjects can be influenced to believe that tDCS will improve cycling performance. Subjects were separated into a belief group (B; 5 women, 6 men) and a disbelief group (DB; 9 women, 3 men). The B group was told that the stimulation would improve performance on a subsequent cycling test. In the DB group, subjects were told that it was not effective and would hinder performance. The cycling test was a 3-minute aerobic test (3mAT) where subjects maintained the highest power output possible for three minutes, after completing a full 20 min warmup. During the warmup, they were given either no stimulation (control) or 2 mA bilateral stimulation over the M1 region. There was a very slight increase in maximal minute power for the B group (0.22%) and a small decrease for the DB group (-1.00%); however, these differences were not significant. No significant differences were found for any of the cycling variables. In conclustion, tDCS was unable to improve performance on the 3mAT. These findings, in conjunction with others, suggest that the acute effect of tDCS is still questionable when aiming to enhance endurance performance.

Abstract Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.

Peripheral artery disease (PAD) is an atherosclerotic disease impacting over 200 million individuals and the prevalence increases with age. PAD occurs when plaque builds up within the peripheral arteries, leading to reduced blood flow and oxygen supply to the outer extremities. Individuals who experience PAD suffer from ischemia, which is typically accompanied by significant damage to skeletal muscles. Additionally, this tissue damage affects mitochondria, causing them to become dysregulated and dysfunctional, resulting in decreased metabolic rates. As there is no known cure for PAD, researchers are exploring potential therapeutic targets by examining coexisting cardiovascular conditions and metabolic risk factors, such as the aging process. Among these comorbidities, type-two diabetes mellitus and obesity are particularly common in PAD cases. These conditions, along with aging itself, are associated with an elevated accumulation of ectopic lipids within skeletal muscles, similar to what is observed in PAD. Researchers have attempted to reduce excess lipid accumulation by increasing the rate of fatty acid beta oxidation. Manipulating acetyl coenzyme A carboxylase 2, a key regulatory protein of fatty acid beta oxidation, has been the primary focus of such research. When acetyl coenzyme A carboxylase 2 is inhibited, it interrupts the conversion of acetyl-CoA into malonyl-CoA, resulting in an increase in the rate of fatty acid beta oxidation. By utilizing samples from PAD patients and applying the pharmacological strategies developed for acetyl coenzyme A carboxylase 2 in diabetes and obesity to PAD, a potential new therapeutic avenue may emerge, offering hope for improved quality of life for individuals suffering from PAD.

Body composition (BC), a measure of body fat mass (FM), lean body mass (LBM), and bone mineral content (BMC), can be used as a predictor of cardiorespiratory fitness (CRF). Prior studies have established a relationship between BC and VO2max in healthy individuals over 35 years of age. However, this relationship is poorly understood in chronic disease populations. The focus of the study was to assess the relationship between BC, cardiorespiratory fitness, and chronic kidney disease (CKD). A cross-sectional analysis was conducted among 24 (9 males and 15 females) individuals diagnosed with mid-spectrum CKD (stages G2–G3b) who completed a health screening, dual-energy X-ray absorptiometry (DEXA) scan, and underwent a VO2max exercise test. Normality tests, descriptive statistics, Pearson’s correlations, t-tests, and ANOVAs were conducted in SAS v.9.4. The average percent body fat (%BF) was 36.28 ± 8.47%, LBM was 109.4 ± 29.1 lb, BMC was 2308.7 ± 735.1 g, and VO2max was 20.13 ± 5.04 mL/kg/min−1. BC was able to predict CRF via VO2max (R2 = 0.721, p < 0.001) and CKD stage (R2 = 0.390, p < 0.017). Positive correlations were observed in LBM (r = 0.750, p < 0.0018) and BMC (r = 0.647, p < 0.001), and negative correlations were observed with FM (r = −0.384, p < 0.032) and %BF (r = −0.802, p < 0.0001). BC was able to predict both CRF and CKD stages, with significant associations observed between BC, VO2max, and CKD stage. The progression of the CKD stage was associated with lower LBM, BMC, and VO2max values, indicating a graded effect of BC on CRF and CKD stage.

The onset of menopause elicits changes in body composition that negatively influence adipokine levels. Consequently, various health risk factors (e.g., cardiovascular disease, osteoporosis, physical inactivity, obesity, arterial hypertension, hypercholesterolemia, sarcopenia) are influenced by adipokines due to changes in body composition after menopause. Thus, improvements in body composition are considered the primary influencer of adipokines. Though several therapeutic interventions (e.g., medication, diet, meditation, exercise) are employed to target changes in body composition, resistance training appears to be more effective in positively improving body composition through changes in lean-muscle mass/fat-mass ratio. However, due to the lack of research, very little is known about adipokines' anti/inflammatory response in postmenopausal women after completing resistance training. Most resistance training studies in postmenopausal women have focused on leptin, adiponectin, and resistin, with limited research assessing other adipokines that are important in metabolic regulation and inflammatory processes. Additionally, the consistency of resistance training protocols as an intervention is not standardized or fully recognized. Therefore, the focus of this review is to establish a more comprehensive understanding of the benefits of resistance training on influencing adipokine levels based on changes to total body composition in postmenopausal women.

Background Endovascular intervention of femoropopliteal chronic total occlusions (CTOs) is technically more complex. However, there is lack of comparative analysis between CTO and non‐CTO femoropopliteal interventions. Methods and Results We report procedural details and outcomes of patients treated for femoropopliteal CTO and non‐CTO lesions in the XLPAD (Excellence in Peripheral Artery Disease) registry (NCT01904851) between 2006 and 2019. Primary outcomes were procedural success and 1‐year major adverse limb events, a composite of all‐cause death, target limb revascularization, or major amputation. Analysis included 2895 patients (CTO: n=1516 patients; non‐CTO: n=1379 patients) with 3658 lesions (CTO: n=1998 lesions; non‐CTO: n=1660 lesions). Conventional balloon angioplasty (20.86% versus 33.48%, P

Aerobic exercise, specifically high-intensity interval exercise (HIIE), and its effects on renal health and filtration (RHF) are not well understood. Several studies support incorporating contemporary biomarkers serum cystatin C (CyC) and urine epidermal growth factor (uEGF) to combat the volatility of serum creatinine (sCr). Using these biomarkers, we examined the acute influences HIIE has on RHF to determine if there is a ceiling effect in healthy populations. The purpose was to determine the influence of an acute bout of HIIE on RHF. Thirty-six participants (n = 22 males; n = 14 females; age 37.6 ± 12.4 years.; BF% 19.2 ± 7.1%; VO2max 41.8 + 7.4 mL/kg/min) completed 30 min of HIIE on a treadmill (80% and 40% of VO2reserve in 3:2 min ratio). Blood and urine samples were obtained under standardized conditions before, 1 h, and 24 h post-exercise. CyC, sCR, uEGF, urine creatinine (uCr), uCr/uEGF ratio, and multiple estimates of glomerular filtration rate (eGFR) Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations were used. The analysis employed paired sample t-tests and repeated measures ANOVAs. CyC, uEGF, uCr, and uCr/uEGF ratio concentrations were not altered between timepoints. sCr increased 1 h post-exercise (p > 0.002) but not at 24 h post-exercise. eGFR decreased in the MDRD and CKD-EPI equations at 1 h (p > 0.012) with no changes at 24 h post-exercise. CyC and sCr/CyC demonstrated no significant changes. CyC and uEGF are not altered by acute HIIE. The results demonstrate a potential ceiling effect in contemporary and traditional biomarkers of RHF, indicating improvements in RHF may be isolated to populations with reduced kidney function.

Adiponectin (adipoq), the most abundant hormone in circulation, has many beneficial effects on the cardiovascular system, in part by preserving the contractile phenotype of vascular smooth muscle cells (VSMCs). However, the lack of adiponectin or its receptor and treatment with recombinant adiponectin have shown contradictory effects on plaque in mice. RNA sequence of Adipoq+/+ and adipoq−/− VSMCs from male aortas identified a critical role for adiponectin in AKT signaling, the extracellular matrix (ECM), and TGF-β signaling. Upregulation of AKT activity mediated proliferation and migration of adipoq−/− cells. Activation of AMPK with metformin or AdipoRon reduced AKT-dependent proliferation and migration of adipoq−/− cells but did not improve the expression of contractile genes. Adiponectin deficiency impaired oxidative phosphorylation (OXPHOS), increased expression of glycolytic enzymes, and elevated mitochondrial reactive oxygen species (ROS) (superoxide, and hydrogen peroxide). Anti-atherogenic mechanisms targeted the ECM in adipoq−/− cells, downregulating MMP2 and 9 and upregulating decorin (DCN) and elastin (ELN). In vivo, the main sex differences in protein expression in aortas involved a more robust upregulation of MMP3 in females than males. Females also showed a reduction in DCN, which was not affected in males. Our study uncovered the AKT/MAPK/TGF-β network as a central regulator of VSMC phenotype.

Peripheral artery disease (PAD) is a disease of atherosclerosis in the lower extremities. PAD carries a massive burden worldwide, while diagnosis and treatment options are often lacking. One of the key points of research in recent years is the involvement of microRNAs (miRNAs), which are short 20-25 nucleotide single-stranded RNAs that can act as negative regulators of post-transcriptional gene expression. Many of these miRNAs have been discovered to be misregulated in PAD patients, suggesting a potential utility as biomarkers for PAD diagnosis. miRNAs have also been shown to play an important role in many different pathophysiological aspects involved in the initiation and progression of the disease including angiogenesis, hypoxia, inflammation, as well as other cellular functions like cell proliferation and migration. The research on miRNAs in PAD has the potential to lead to a whole new class of diagnostic tools and treatments.

Different levels of arterial occlusive disease (aortoiliac, femoropopliteal, multi-level disease) can produce claudication symptoms in different leg muscle groups (buttocks, thighs, calves) in patients with peripheral artery disease (PAD). We tested the hypothesis that different locations of occlusive disease uniquely affect the muscles of PAD legs and produce distinctive patterns in the way claudicating patients walk. Ninety-seven PAD patients and 35 healthy controls were recruited. PAD patients were categorized to aortoiliac, femoropopliteal and multi-level disease groups using computerized tomographic angiography. Subjects performed walking trials both pain-free and during claudication pain and joint kinematics, kinetics, and spatiotemporal parameters were calculated to evaluate the net contribution of the calf, thigh and buttock muscles. PAD patients with occlusive disease affecting different segments of the arterial tree (aortoiliac, femoropopliteal, multi-level disease) presented with symptoms affecting different muscle groups of the lower extremity (calves, thighs and buttocks alone or in combination). However, no significant biomechanical differences were found between PAD groups during the pain-free conditions with minimal differences between PAD groups in the claudicating state. All statistical differences in the pain-free condition occurred between healthy controls and one or more PAD groups. A discriminant analysis function was able to adequately predict if a subject was a control with over 70% accuracy, but the function was unable to differentiate between PAD groups. In-depth gait analyses of claudicating PAD patients indicate that different locations of arterial disease produce claudication symptoms that affect different muscle groups across the lower extremity but impact the function of the leg muscles in a diffuse manner generating similar walking impairments.

Sport cultures transmit values for anticipated conduct. Recent events have resulted in injuries/deaths of National Collegiate Athletic Association (NCAA) student-athletes, usually during off-season football training. Through media reports, strength and conditioning coaches (SCC) have been allegedly involved by incorporating military-style training (MST). Mental toughness (MT) has been associated with hypermasculine subcultures in sports. For the first time, perceptions of collegiate SCCs were chosen to contribute to the development of cultural best practices in sports, via a multiphase mixed-method design (Phase 1, n = 465; Phase 2, n = 72; Phase 3, n = 99). Quantitative and qualitative data were collected aiming to confirm and explore the use of MST in the NCAA, its connection to SCCs, its association with MT development, and the role of the media. MST is uncommon in the NCAA. MST takes place mostly during the off-season in the form of physical, in-scope protocols while football is the most common sport. MST promotes MT. The recent media backlash is considered unfounded. Cultures promoted by SCCs do not indicate conformity of student-athletes to unethical/unhealthy expectations. Future sport psychology research and practice should continue to prioritize culture, cultural identities, and physical and mental well-being.

Objective To investigate the efficacy of interventions designed to train and develop mental toughness (MT) in sport.Design Systematic review and meta-analysis.Data sources Journal articles, conference papers and doctoral theses indexed in Embase, Scopus, PubMed and SPORTDiscus from inception to 22 November 2019.Eligibility criteria for selecting studies Observational and pre–post experimental designs on the efficacy of physical and/or psychological interventions designed to promote MT in athletes.Results A total of 12 studies, published between 2005 and 2019, were included in the review. A majority of the studies included a sample comprised exclusively of male athletes (54.55%), MT interventions were primarily psychological (83.33%) and most studies measured MT via self-report (75%). The Psychological Performance Inventory (25%), the Mental Toughness Questionnaire-48 (16.67%), and the Mental, Emotional and Bodily Toughness Inventory (16.67%) were the most popular inventories used to measure MT. Methodological quality assessments for controlled intervention studies (k=7), single group pre-test–post-test designs (k=4) and single-subject designs (k=1) indicated that the risk of bias was high in most (75%) of the studies. The meta-analysis involving k=10 studies revealed a large effect (d=0.80, 95% CI 0.30 to 1.28), with variability across studies estimated at 0.56.Conclusion Although the findings of this review suggest there are effective, empirically based interventions designed to train MT in sport, practitioners should be aware of the level of validity of intervention research before adopting any of the MT training programmes reported in the applied sport psychology literature.

Recent tragic events and data from official NCAA reports suggest student-athletes' well-being is compromised by symptoms of mental health (MH) disorders. Self-compassion (SC) and mental toughness (MT) are two psychological constructs that have been shown effective against stressors associated with sports. The purpose of this study was to investigate SC, MT, and MH in a NCAA environment for the first time and provide practical suggestions for MH best practice No.4. In total, 542 student-athletes participated across Divisions (Mage = 19.84, SD = 1.7). Data were collected through Mental Toughness Index, Self-Compassion Scale, and Mental Health Continuum-Short Form. MT, SC (including mindfulness), and MH were positively correlated. Males scored higher than females on all three scales. No differences were found between divisions. SC partially mediated the MT-MH relationship, but moderation was not significant. Working towards NCAA MH best practice should include training athletes in both MT and SC skills (via mindfulness).

Aerobic exercise elicits a multitude of physiological improvements in both healthy and diseased populations. However, acute changes in renal health and filtration with aerobic exercise remain difficult to quantify by traditional biomarkers to estimate glomerular filtration rate (eGFR). This study aimed to determine if an acute bout of moderate-intensity aerobic exercise transiently improves non-traditional biomarkers when compared to traditional biomarkers of renal health and filtration in individuals without cardiometabolic diseases. Thirty-nine participants (n = 18 men; n = 21 women; age 32.5 + 12.6 yr; height 171.1 + 11.4 cm; weight 78.7 + 15.6 kg; BMI 27.1 + 5.8) completed a single bout of moderate-intensity (50–60% HRR) aerobic exercise. Blood and urine samples were collected and compared before and post-exercise. Serum creatinine, urine epidermal growth factor (uEGF), uEGF/urine creatinine ratio (uEGFR), and cystatin C (CyC) were measured. In addition, eGFR-MDRD and the CKD-epidemiology equations were used to analyze renal clearance. Relative to pre-exercise measures: serum creatinine (p = 0.26), uEGF (p = 0.35), and uEGFR (p = 0.09) remained unchanged, whereas cystatin C (p = 0.00) significantly increased post-exercise. CyC eGFR was the only estimator of renal filtration to significantly change (p = 0.04). In conclusion, CyC is the only biomarker of renal health and filtration to significantly increase after aerobic exercise. Further investigation focused on sampling time and exercise-intensity is needed to solidify the current understanding of renal health and filtration.

Hydrogen sulfide (H2S) is an endogenous signaling molecule which is important for cardiovascular health, but its mechanism of action remains poorly understood. Here, we report measurements of H2S as well as its oxidized metabolites, termed small oxoacids of sulfur (SOS = HSOH and HOSOH), in four human primary vascular cell lines: smooth muscle and endothelial cells derived from both human arterial and coronary tissues. We use a methodology that targets small molecular weight sulfur species; mass spectrometric analysis allows for species quantification to report cellular concentrations based on an H2S calibration curve. The production of H2S and SOS is orders of magnitude higher in smooth muscle (nanomolar) as compared to endothelial cell lines (picomolar). In all the primary lines measured, the distributions of these three species were HOSOH >H2S > HSOH, with much higher SOS than seen previously in non-vascular cell lines. H2S and SOS were effluxed from smooth muscle cells in higher concentrations than endothelial cells. Aortic smooth muscle cells were used to examine changes under hypoxic growth conditions. Hypoxia caused notable increases in HSOH and ROS, which we attribute to enhanced sulfide quinone oxidase activity that results in reverse electron transport.

Peripheral artery disease (PAD) pathophysiology extends beyond hemodynamics to include other operating mechanisms, including endothelial dysfunction. Oxidative stress may be linked to endothelial dysfunction by reducing nitric oxide (NO) bioavailability. We aimed to investigate whether the NO system and its regulators are altered in the setting of PAD and to assess the relationship between NO bioavailability and oxidative stress. Sera from 35 patients with intermittent claudication (IC), 26 patients with critical limb ischemia (CLI), and 35 non-PAD controls were analyzed to determine levels of tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), nitrate/nitrite (nitric oxides, or NOx), arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the oxidative stress markers 8-Oxo-2′-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), advanced glycation end products (AGEs), and protein carbonyls. NOx was significantly lower in IC and CLI patients compared to controls in association with elevated oxidative stress, with the greatest NOx reductions observed in CLI. Compared with controls, IC and CLI patients had reduced BH4, elevated BH2, and a reduced BH4/BH2 ratio. SDMA, the arginine/SDMA ratio, and the arginine/ADMA ratio were significantly higher in CLI patients. The NO system and its regulators are significantly compromised in PAD. This dysregulation appears to be driven by increased oxidative stress and worsens as the disease progresses from claudication to CLI.

[This corrects the article DOI: 10.1371/journal.pone.0186603.].

Thoracic aortic aneurysm and dissection are life-threatening complications of Marfan syndrome (MFS). Studies of human and mouse aortic samples from late stage MFS demonstrate increased TGF-β activation/signaling and diffuse matrix changes. However, the role of the aortic smooth muscle cell (SMC) phenotype in early aneurysm formation in MFS has yet to be fully elucidated. As our objective, we investigated whether an altered aortic SMC phenotype plays a role in aneurysm formation in MFS. We describe previously unrecognized concordant findings in the aortas of a murine model of MFS, mgR, during a critical and dynamic phase of early development. Using Western blot, gelatin zymography, and histological analysis, we demonstrated that at postnatal day (PD) 7, before aortic TGF-β levels are increased, there is elastic fiber fragmentation/disorganization and increased levels of MMP-2 and MMP-9. Compared to wild type (WT) littermates, aortic SMCs in mgR mice express higher levels of contractile proteins suggesting a switch to a more mature contractile phenotype. In addition, tropoelastin levels are decreased in mgR mice, a finding consistent with a premature switch to a contractile phenotype. Proliferation assays indicate a decrease in the proliferation rate of mgR cultured SMCs compared to WT SMCs. KLF4, a regulator of smooth muscle cell phenotype, was decreased in aortic tissue of mgR mice. Finally, overexpression of KLF4 partially reversed this phenotypic change in the Marfan SMCs. This study indicates that an early phenotypic switch appears to be associated with initiation of important metabolic changes in SMCs that contribute to subsequent pathology in MFS.

Background: Peripheral artery disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in the arteries supplying the legs, affects approximately 5% of Americans. We have previously, demonstrated that a myopathy characterized by myofiber oxidative damage and degeneration is central to PAD pathophysiology. Objectives: In this study, we hypothesized that increased oxidative damage in the myofibers of the gastrocnemius of PAD patients is myofiber-type selective and correlates with reduced myofiber size. Methods: Needle biopsies were taken from the gastrocnemius of 53 PAD patients (28 with early PAD and 25 with advanced PAD) and 25 controls. Carbonyl groups (marker of oxidative damage), were quantified in myofibers of slide-mounted tissue, by quantitative fluorescence microscopy. Myofiber cross-sectional area was determined from sarcolemma labeled with wheat germ agglutinin. The tissues were also labeled for myosin I and II, permitting quantification of oxidative damage to and relative frequency of the different myofiber Types (Type I, Type II and mixed Type I/II myofibers). We compared PAD patients in early (N=28) vs. advanced (N=25) disease stage for selective, myofiber oxidative damage and altered morphometrics. Results: The carbonyl content of gastrocnemius myofibers was higher in PAD patients compared to control subjects, for all three myofiber types (p