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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.

The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, including histone H3K9 di/tri-methylation and HP1, decrease with age in muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor S-adenosylmethionine (SAM). We find that restoration of intracellular SAM in aged MuSCs restores heterochromatin content to youthful levels and rejuvenates age-associated features, including DNA damage accumulation, increased cell death, and defective muscle regeneration. SAM is not only a methyl group donor for transmethylation, but it is also an aminopropyl donor for polyamine synthesis. Excessive consumption of SAM in polyamine synthesis may reduce its availability for transmethylation. Consistent with this premise, we observe that perturbation of increased polyamine synthesis by inhibiting spermidine synthase restores intracellular SAM content and heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity in male and female mice. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during murine MuSC ageing.

BACKGROUND: Comprehensive descriptions of equids with granulocytic anaplasmosis (EGA) with neurologic or muscle disease and other atypical presentations are scarce in the literature. OBJECTIVE: Describe the clinical signs, laboratory findings, treatment, and outcome of equids with EGA with emphasis on neurologic and muscle disease. ANIMALS: Thirty-eight horses, 1 donkey. METHODS: Retrospective study. Equids with EGA were included. The electronic data base was searched from January 2000 to December 2022 using the words anaplasmosis, ehrlichiosis, granulocytic, and rickettsia. Signalment and clinical data were reviewed. Data were evaluated for normality using Shapiro-Wilk test. Parametric and nonparametric statistics were used for normally and non-normally distributed data. RESULTS: Common (41%) and other (59%) presentations were seen in horses ≥ 4 years of age (median, 14 years) with an overrepresentation of males (77%). Neurologic disease was common (41%), mainly presenting as diffuse symmetrical proprioceptive ataxia. Brain disease was less common manifesting as obtundation and cranial nerve deficits. Muscle disease was less common, with QH breeds with the variant causing myosin heavy chain myopathy (MYHM) having severe disease. Cavitary effusion, cardiomyopathy and disseminated intravascular coagulation (DIC) were uncommon. Clinical laboratory results varied depending on disease stage. Muscle enzyme activities were significantly higher in horses with muscle disease. Outcome was favorable with prompt tetracycline treatment. Death and long-term sequelae were not reported. CONCLUSIONS AND CLINICAL IMPORTANCE: Common and atypical presentations of EGA have a favorable outcome with prompt tetracycline treatment. Quarter horse breeds with muscle disease should be genotyped for MYHM.

We examined if an interaction exists between bone and muscle in predicting fractures in older men. Prospective data from the Osteoporotic Fractures in Men study was used to build Cox proportional hazards models. Predictors included HR-pQCT total volumetric BMD (Tt.BMD), trabecular BMD (Tb.BMD), cortical BMD (Ct.BMD) and cortical area (Ct.Ar) at distal radius/tibia, HR-pQCT muscle volume and density (diaphyseal tibia), D3 -creatine dilution (D3 Cr) muscle mass, and grip strength and leg force, analyzed as continuous variables and as quartiles. Incident fractures were self-reported every 4 months via questionnaires and centrally adjudicated by physician review of radiology reports. Potential confounders (demographics, comorbidities, lifestyle factors, etc.) were considered. A total of 1353 men (mean age 84.2 ± 4.0 years, 92.7% white) were followed for 6.03 ± 2.11 years. In the unadjusted (continuous) model, there were no interactions (p > 0.05) between any muscle variable (D3 Cr muscle mass, muscle volume, muscle density, grip strength or leg force) and Tt.BMD at distal radius/tibia for fractures (all: n = 182-302; nonvertebral: n = 149-254; vertebral: n = 27-45). No consistent interactions were observed when interchanging Tt.BMD for Tb.BMD/Ct.BMD or for Ct.Ar (bone structure) at the distal radius/tibia in the unadjusted (continuous) models. Compared with men in quartiles (Q) 2-4 of D3 Cr muscle mass and Q2-4 of distal tibia Tt.BMD, men in Q1 of both had increased risk for all fractures (hazard ratio (HR) = 2.00; 95% confidence interval [CI] 1.24-3.23, p = 0.005) and nonvertebral fractures (HR = 2.10; 95% CI 1.25-3.52, p  0.05) when visually inspecting other quartile groups in the multivariable-adjusted model. In this prospective cohort study of older men, there was no consistent interactions between bone and muscle variables on fracture risk. Larger sample sizes and longer follow-up may be needed to clarify if there is an interaction between bone and muscle on fracture risk in men. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

ObjectivesSerum creatinine-based estimated glomerular filtration rate equations and muscle mass are powerful markers of health and mortality risk. However, the serum creatinine-to-cystatin-C ratio may be a better indicator of health status. The objective of this study was to describe the relationship between creatinine-to-cystatin-C ratio and all-cause mortality when stratifying patients as per race and as per chronic kidney disease status.MethodsThis was a retrospective cohort study examining black and nonblack US veterans between October 2004 and September 2019, with baseline cystatin C and creatinine data from those not on dialysis during the study period. Veterans were divided into four creatinine-to-cystatin-C ratio groups:

Muscle dysmorphia (MD) is characterized by a pervasive belief or fear of insufficient muscularity and an elevated drive for muscularity, representing the pathological and extreme pursuit of muscularity. Psychometric properties of one of the most widely used measures of MD symptoms-the Muscle Dysmorphic Disorder Inventory (MDDI)-have yet to be evaluated in transgender men despite emerging evidence suggesting differential risk for MD symptoms in this population. In this study, we assessed the psychometric properties of the MDDI in a sample of 330 transgender men ages 18-67 years who participated in a large-scale national longitudinal cohort study of sexual and gender minority adults in the U.S. Using a two-step, split-sample approach, an initial exploratory factor analysis supported a three-factor structure and a subsequent confirmatory factor analysis of a re-specified three-factor model demonstrated good overall fit (χ2/df = 1.84, CFI =0.94, TLI =0.92, RMSEA =0.07 [90% CI =0.05,.09], SRMR =0.08). Moreover, results supported the internal consistency and convergent validity of the MDDI subscales in transgender men. Findings inform the use of the MDDI among transgender men and provide a foundation to support further work on the MDDI and MD symptoms among gender minority populations.

Grip strength is a valuable preclinical assay to study muscle physiology in disease and aging by directly determining changes in muscle force generation in active laboratory mice. Existing methods to statistically evaluate grip strength, however, have limitations in the power and scope of the physiological features that are assessed. We therefore designed a microcontroller whose serial measure of resistance-based force enables the simultaneous readout of (1) peak grip strength, (2) force profile (the non-linear progress of force exerted throughout a standard grip strength trial), and (3) cumulative force profile (the integral of force with respect to time of a single grip strength trial). We hypothesized that muscle pathologies of different etiologies have distinct effects on these parameters. To test this, we used our apparatus to assess the three muscle parameters in mice with impaired muscle function resulting from surgically induced peripheral pain, genetic peripheral neuropathy, adverse muscle effects induced by statin drug, and metabolic alterations induced by a high-fat diet. Both surgically induced peripheral nerve injury and statin-associated muscle damage diminished grip strength and force profile, without affecting cumulative force profile. Conversely, genetic peripheral neuropathy resulting from lipin 1 deficiency led to a marked reduction to all three parameters. A chronic high-fat diet led to reduced grip strength and force profile when normalized to body weight. In high-fat fed mice that were exerted aerobically and allowed to recover for 30 min, male mice exhibited impaired force profile parameters, which female mice were more resilient. Thus, simultaneous analysis of peak grip strength, force profile and cumulative force profile distinguishes the muscle impairments that result from distinct perturbations and may reflect distinct motor unit recruitment strategies.

Low vertebral bone mass is a major risk factor for vertebral compression fractures. Although sarcopenia has been shown to be associated with low bone mineral density (BMD), it is not known whether trunk musculature is directly associated with lumbar BMD, and whether exercise modifies this association. Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), we sought to determine the association of muscle density and fat fraction of the psoas, paraspinal, and oblique muscle groups with L3 lumbar volumetric BMD, and whether these associations were modified by exercise. We obtained L3 vBMD measurements, and fat and muscle measurements (in Hounsfield units [HU]) from abdominal computed tomography (CT) scans spanning the L2 -L4 intervertebral disc spaces. Muscle density was defined as the mean HU value for a muscle group area. Fat fraction was calculated as the mean HU value for the muscle group fat area/total muscle group area (cm2 ). Exercise data were self-reported (MET-minute/week). We utilized multivariable linear regression to evaluate these associations, stratified by gender, and adjusting for demographics, body mass index (BMI), smoking status, impaired fasting glucose, and corticosteroid and anti-resorptive medication use. Among 1923 MESA participants, mean ± standard deviation (SD) age was 62 ± 10 years, 49% were female, 40% white, 21% black, 26% Hispanic/Latino, and 13% Chinese. In fully adjusted analysis, for every 1-SD higher psoas fat fraction, there was a 3.19-SD lower L3 vBMD in men and 4.3-SD lower L3 vBMD in women (p

This study examined relationship status (e.g., single versus not single) and number of sexual partners in relation to muscularity- and disordered eating-related attitudes and behaviors among 1090 cisgender gay men enrolled in The PRIDE Study in 2018. Participants completed measures assessing muscle dysmorphia (MD) symptoms, disordered eating attitudes and behaviors, and appearance- and performance-enhancing drug or supplement (APEDS) use. In linear regression models adjusting for theoretically relevant covariates, neither relationship status nor number of past-month sexual partners was associated with disordered eating attitudes. In terms of MD symptoms, single (versus not single) relationship status was associated with greater appearance intolerance, and a greater number of sexual partners was associated with greater drive for size and functional impairment. In adjusted logistic regression models, a greater number of past-month sexual partners was associated with use of anabolic-androgenic steroids, synthetic performance-enhancing substances, protein supplements, and creatine supplements, as well as greater likelihood of engaging in compelled/driven exercise. Across all associations, effect sizes were generally small. Overall, results support that inquiring about sexual partners may have utility in evaluating risk for muscularity-oriented attitudes and behaviors among cisgender gay men. Future work will need to replicate these findings, particularly in more diverse samples.

OBJECTIVE: Appearance and performance-enhancing drugs and supplements (APEDS) can be used to enhance muscle growth, athletic performance, and physical appearance. The aim of this study was to examine the lifetime use of APEDS and associations with eating disorder and muscle dysmorphia symptoms among gender minority people. METHOD: Participants were 1653 gender minority individuals (1120 gender-expansive [defined as a broad range of gender identities that are generally situated outside of the woman-man gender binary, e.g., genderqueer, nonbinary] people, 352 transgender men, and 181 transgender women) recruited from The Population Research in Identity and Disparities for Equality Study in 2018. Regression analyses stratified by gender identity examined associations of any APEDS use with eating disorder and muscle dysmorphia symptom scores. RESULTS: Lifetime APEDS use was common across groups (30.7% of gender-expansive people, 45.2% of transgender men, and 14.9% of transgender women). Protein supplements and creatine supplements were the most commonly used APEDS. Among gender-expansive people and transgender men, lifetime use of any APEDS was significantly associated with higher eating disorder scores, dietary restraint, binge eating, compelled/driven exercise, and muscle dysmorphia symptoms. Any APEDS use was additionally associated with laxative use among gender-expansive people. Among transgender women, use of any APEDS was not significantly associated with eating disorder or muscle dysmorphia symptoms. DISCUSSION: APEDS use is common and associated with eating disorder and muscle dysmorphia symptoms in gender-expansive people and transgender men, thus highlighting the importance of assessing for these behaviors and symptoms among these populations, particularly in clinical settings. PUBLIC SIGNIFICANCE: This study aimed to examine APEDS use among gender minority people. We found that 30.7% of gender-expansive (e.g., nonbinary) people, 45.2% of transgender men, and 14.9% of transgender women reported lifetime APEDS use, which was associated with eating disorder and muscle dysmorphia symptoms in transgender men and gender-expansive people. Clinicians should assess for these behaviors in gender minority populations.

BackgroundMuscle mass declines with age, while body adiposity increases. Sarcopenic obesity has been proposed to be particularly deleterious. However, previous methods for estimating muscle mass have been inadequate, and the relative contributions of total body fat versus muscle fat to adverse outcomes have been unclear.MethodIn a large cohort of older men (N = 1 017), we measured muscle mass (D3-creatine dilution), muscle density (high-resolution peripheral quantitative computed tomography in the diaphyseal tibia) as a proxy of muscle fat, and total body fat (dual-energy x-ray absorptiometry). We examined their associations with physical performance (walking speed, grip strength, chair stand time), the risk of mobility outcomes (mobility limitations, mobility disability), and the risk of death over ~5 years.ResultsIn combined models, lower muscle mass and muscle density were independently associated with worse physical performance and the risk of adverse outcomes, while total body fat was minimally related to physical performance and not related to mobility outcomes or mortality. For example, the relative risks for mortality per 1 standardized unit increase in muscle density, muscle mass, and total body fat were 0.84 (95% confidence interval: 0.74, 0.96), 0.70 (0.57, 0.86), and 0.90 (0.64, 1.25), respectively.ConclusionsMuscle mass and muscle density were associated with physical performance and adverse outcomes, and had independent, additive effects. There was little additional contribution of total body fat.

PURPOSE: Appearance and performance-enhancing drugs and supplements (APEDS) are used to enhance muscle growth, athletic performance, and physical appearance. The aim of this study was to examine the lifetime use of APEDS and associations with eating disorder and muscle dysmorphia symptoms among cisgender sexual minority people. METHODS: Participants were cisgender sexual minority people (1090 gay men, 100 bisexual plus men, 564 lesbian women, and 507 bisexual plus women) recruited from The PRIDE Study in 2018 who reported lifetime APEDS use and completed the Eating Disorder Examination-Questionnaire (EDE-Q) and the Muscle Dysmorphic Disorder Inventory (MDDI). Regression analyses stratified by gender and sexual orientation examined associations of any APEDS use with EDE-Q and MDDI scores. RESULTS: Lifetime APEDS use was common across the four groups of cisgender sexual minority people (44% of gay men, 42% of bisexual plus men, 29% of lesbian women, and 30% of bisexual plus women). Protein supplements and creatine supplements were the most commonly used APEDS. Any APEDS use was associated with higher EDE-Q scores on one or more subscales in all sexual minority groups. Further, any APEDS use was associated with higher MDDI Total Scores in all groups; any APEDS use was associated with all MDDI subscale scores in cisgender gay men only. DISCUSSION: APEDS use is common and associated with eating disorder and muscle dysmorphia symptoms in sexual minority men and women, thus highlighting the importance of assessing for these behaviors and symptoms among these populations in clinical settings.

BackgroundRepresenting the pathological extreme pursuit of muscularity, muscle dysmorphia (MD) is characterized by a pervasive belief or fear around insufficient muscularity and an elevated drive for muscularity. Despite evidence of elevated body image-related concerns among sexual minority populations, little is known about the degree of muscle dysmorphia (MD) symptoms among sexual minorities, particularly based on Muscle Dysmorphic Disorder Inventory (MDDI) scores. The objective of this study was to examine the nature and severity of MD symptoms in cisgender sexual minority men and women and provide community norms of the MDDI for these populations.MethodsData from participants in The PRIDE Study, an existing study of health outcomes in sexual and gender minority people from the United States, were examined. Participants included cisgender gay men (N = 1090), cisgender bisexual plus (bisexual, pansexual, and/or polysexual) men (N = 100), cisgender lesbian women (N = 563), and cisgender bisexual plus women (N = 507). We calculated means, standard deviations (SD), and percentiles for the MDDI total and subscale scores for cisgender sexual minority men and women. We compared MDDI scores by sexual orientation using linear regression models, both unadjusted and adjusted for sociodemographics.ResultsOverall, the sample was 85.2% White, 3.0% Asian or Pacific Islander, 2.0% Black, 0.5% Native American, 3.9% multiracial, and 6.6% Hispanic/Latino/a. The mean age was 38.6 (SD = 14.3) and 69.4% had a college degree or higher. Means (SD) for the MDDI total score were 27.4 (7.7) for cisgender gay men, 26.4 (6.4) for cisgender bisexual plus men, 24.3 (6.1) for cisgender lesbian women, and 24.6 (5.5) for cisgender bisexual plus women. There were no significant differences in MDDI scores between cisgender gay and bisexual plus men, or between cisgender lesbian women and bisexual plus women in unadjusted or adjusted models.ConclusionsThese normative data provide insights into the experience of MD symptoms among cisgender sexual minority men and women and can aid researchers and clinicians in the evaluation of MD symptoms and interpretation of MDDI scores in sexual minority populations.

Despite increasing empirical interest in muscle dysmorphia (MD), a dearth of research has assessed this construct in sexual minority populations. In particular, the psychometric properties of one of the most widely used measures of MD symptoms-the Muscle Dysmorphic Disorder Inventory (MDDI)-have not been evaluated in sexual minority populations despite emerging evidence suggesting differential risk for MD symptoms across sexual orientation groups. In this study, we assessed the psychometric properties of the MDDI in a sample of 715 cisgender gay men and 404 cisgender lesbian women ages 18-50 years who participated in a large-scale national longitudinal cohort study of sexual and gender minority adults. The factor structure of the MDDI was examined in each sample using a two-step, split-sample exploratory and confirmatory factor analytic approach. Exploratory factor analysis supported a three-factor structure in both samples, which were confirmed by confirmatory factor analysis. Moreover, results supported the internal consistency reliability and convergent validity of the MDDI subscales in both samples. Cumulatively, these findings suggest that the MDDI is an appropriate measure of MD symptoms among cisgender gay men and cisgender lesbian women.

Ischemia-reperfusion injury (IRI) is a critical condition associated with serious clinical manifestations. Extensive research has focused on the strategies increasing organ tolerance to IRI. Preconditioning (PC) has been shown to provide protection to various organs toward IRI. However, the underlying mechanisms remain unknown. This study aimed to evaluate the role of PC on muscle regeneration after IRI and the potential underlying mechanisms. Three-month-old male UCP-1 reporter mice underwent unilateral hindlimb IRI with or without PC, the tissue viability and injury index were measured at 24 h after IRI. Hindlimb gait, muscle contractility, muscle histology were analyzed at 2 weeks after IRI. In another group of animals, β3 adrenergic receptor (β3AR) agonist amibegron and β3AR antagonist SR-59230A were administrated before PC/IRI, the hindlimb function and muscle regeneration were evaluated at 2 weeks after IRI. Our results showed that PC has little effect on improving the tissue viability at the acute phase of IRI, but it showed a long-term beneficial role of improving hindlimb function and muscle regeneration as evidenced by increased central nuclei regenerating myofibers. The effects of PC are related to inducing muscle fibro-adipogenic progenitor (FAP) brown/beige-like adipocyte (BAT) differentiation. Amibegron treatment displayed a similar role of PC while SR-59230A abolished the effect of PC. This study suggests PC has a beneficial role in promoting muscle regeneration after IRI through β3AR signaling pathway-stimulated FAP-BAT differentiation.

The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and reduces adiposity. Skeletal muscle contributes to preventing adiposity, by consuming nearly half the energy of a typical human. We report sexually dimorphic differences in energy metabolism and muscle function in Rdh10+/- mice. Relative to wild-type (WT) controls, Rdh10+/- males fed a high-fat diet decrease reliance on fatty-acid oxidation and experience glucose intolerance and insulin resistance. Running endurance decreases 40%. Rdh10+/- females fed this diet increase fatty acid oxidation and experience neither glucose intolerance nor insulin resistance. Running endurance increases 220%. We therefore assessed RA function in the mixed-fiber type gastrocnemius muscles (GM), which contribute to running, rather than standing, and are similar to human GM. RA levels in Rdh10+/- male GM decrease 38% relative to WT. Rdh10+/- male GM increase expression of Myog and reduce Eif6 mRNAs, which reduce and enhance running endurance, respectively. Cox5A, complex IV activity, and ATP decrease. Increased centralized nuclei reveal existence of muscle malady and/or repair in GM fibers. Comparatively, RA in Rdh10+/- female GM decreases by less than half the male decrease, from a more modest decrease in Rdh10 and an increase in the estrogen-induced retinol dehydrogenase Dhrs9. Myog mRNA decreases. Cox5A, complex IV activity, and ATP increase. Centralized GM nuclei do not increase. We conclude that Rdh10/RA affects whole body energy use and insulin resistance partially through sexual dimorphic effects on skeletal muscle gene expression, structure, and mitochondria activity.

BACKGROUND: Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. METHOD: In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumours following neoadjuvant chemotherapy or pT3-4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. FINDINGS: Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2-29·8). Median disease-free survival was 19·4 months (95% CI 15·9-24·8) with atezolizumab and 16·6 months (11·2-24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. INTERPRETATION: To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. FUNDING: F Hoffmann-La Roche/Genentech.

As exercise intensity exceeds 65% of maximal oxygen uptake carbohydrate energy sources predominate. However, relative to the meager 4-5 g blood glucose pool size in a postabsorptive individual (0.9-1.0 g·L-1 × 5 L blood = 18-20 kcal), carbohydrate (CHO) oxidation rates of 20 kcal·min-1 can be sustained in a healthy and fit person for one hour, if not longer, all the while euglycemia is maintained. While glucose rate of appearance (i.e., production, Ra) from splanchnic sources in a postabsorptive person can rise 2-3 fold during exercise, working muscle and adipose tissue glucose uptake must be restricted while other energy substrates such as glycogen, lactate, and fatty acids are mobilized and utilized. If not for the use of alternative energy substrates hypoglycemia would occur in less than a minute during hard exercise because blood glucose disposal rate (Rd) could easily exceed glucose production (Ra) from hepatic glycogenolysis and gluconeogenesis. The goal of this paper is to present and discuss the integration of physiological, neuroendocrine, circulatory, and biochemical mechanisms necessary for maintenance of euglycemia during sustained hard physical exercise.

Clostridium perfringens type A is involved in gas gangrene in humans and animals. Following a traumatic injury, rapid bacterial proliferation and exotoxin production result in severe myonecrosis. C. perfringens alpha toxin (CPA) and perfringolysin (PFO) are the main virulence factors responsible for the disease. Recent in vitro studies have identified an Agr-like quorum-sensing (QS) system in C. perfringens that regulates the production of both toxins. The system is composed of an AgrB membrane transporter and an AgrD peptide that interacts with a two-component regulatory system in response to fluctuations in the cell population density. In addition, a synthetic peptide named 6-R has been shown to interfere with this signaling mechanism, affecting the function of the Agr-like QS system in vitro In the present study, C. perfringens type A strain ATCC 3624 and an isogenic agrB-null mutant were tested in a mouse model of gas gangrene. When mice were intramuscularly challenged with 106 CFU of wild-type ATCC 3624, severe myonecrosis and leukocyte aggregation occurred by 4 h. Similar numbers of an agrB-null mutant strain produced significantly less severe changes in the skeletal muscle of challenged mice. Complementation of the mutant to regain agrB expression restored virulence to wild-type levels. The burdens of all three C. perfringens strains in infected muscle were similar. In addition, animals injected intramuscularly with wild-type ATCC 3624 coincubated with the 6-R peptide developed less severe microscopic changes. This study provides the first in vivo evidence that the Agr-like QS system is important for C. perfringens type A-mediated gas gangrene.IMPORTANCE Clostridium perfringens type A strains produce toxins that are responsible for clostridial myonecrosis, also known as gas gangrene. Toxin production is regulated by an Agr-like quorum-sensing (QS) system that responds to changes in cell population density. In this study, we investigated the importance of this QS system in a mouse model of gas gangrene. Mice challenged with a C. perfringens strain with a nonfunctional regulatory system developed less severe changes in the injected skeletal muscle compared to animals receiving the wild-type strain. In addition, a synthetic peptide was able to decrease the effects of the QS in this disease model. These studies provide new understanding of the pathogenesis of gas gangrene and identified a potential therapeutic target to prevent the disease.

RationaleCocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD).ObjectiveIn a phase II randomized clinical trial, to assess whether 6 months of cocoa improved walking performance in people with PAD, compared with placebo.Methods and resultsSix-month double-blind, randomized clinical trial in which participants with PAD were randomized to either cocoa beverage versus placebo beverage. The cocoa beverage contained 15 g of cocoa and 75 mg of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The 2 primary outcomes were 6-month change in 6-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A 1-sided P

Unpaired ligands are secreted signals that act via a GP130-like receptor, domeless, to activate JAK/STAT signalling in Drosophila. Like many mammalian cytokines, unpaireds can be activated by infection and other stresses and can promote insulin resistance in target tissues. However, the importance of this effect in non-inflammatory physiology is unknown. Here, we identify a requirement for unpaired-JAK signalling as a metabolic regulator in healthy adult Drosophila muscle. Adult muscles show basal JAK-STAT signalling activity in the absence of any immune challenge. Plasmatocytes (Drosophila macrophages) are an important source of this tonic signal. Loss of the dome receptor on adult muscles significantly reduces lifespan and causes local and systemic metabolic pathology. These pathologies result from hyperactivation of AKT and consequent deregulation of metabolism. Thus, we identify a cytokine signal that must be received in muscle to control AKT activity and metabolic homeostasis.

mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1KO) reduces muscle mass. PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity.

REASONS FOR PERFORMING STUDY:Although muscle mass strongly influences performance, there is currently no effective means to measure the 3-dimensional muscle mass of horses. We evaluated a 3-dimensional (3D) scanning methodology for its ability to quantify torso and hindquarter volumes as a proxy for regional muscle mass in horses. OBJECTIVES:Determine the repeatability of 3D scanning volume (V) measurements and their correlation to body weight, estimated body volume and muscle/fat ultrasound (US) depth. METHODS:Handheld 3D photonic scans were performed on 16 Quarter Horses of known body weight 56 days apart (n = 32 scans) with each scan performed in duplicate (n = 32 replicates). Tail head fat, gluteal and longissimus dorsi muscle depths were measured using US. Processed scans were cropped to isolate hindquarter (above hock, caudal to tuber coxae) and torso (hindquarter plus dorsal thoracolumbar region) segments and algorithms used to calculate V. Torso and hindquarter volume were correlated with body weight and US using Pearson's correlation and with estimated torso volume (50% body weight / body density) with Bland-Altman analysis. RESULTS:Scans took 2 min with < 3.5% error for duplicate scans. Torso volume (R = 0.90, P< 0.001) and hindquarter volume (R = 0.82, P< 0.001) strongly correlated with body weight and estimated BV (R = 0.91) with low bias. Torso volume moderately correlated to mean muscle US depth (R = 0.4, P< 0.05) and tail head fat (R = 0.42, P< 0.01). Mean muscle US depth moderately correlated to body weight (R = 0.50, P< 0.01). MAIN LIMITATIONS:3D Scans determine body volume not muscle volume. CONCLUSIONS:The hand-held 3D scan provided a rapid repeatable assessment of torso and hindquarter volume strongly correlated to body weight and estimated volume. Superimposition of regional scans and volume measures could provide a practical means to follow muscle development when tail head fat depth remain constant.

We describe the anatomy of all the primary motor neurons in the fly proboscis and characterize their contributions to its diverse reaching movements. Pairing this behavior with the wealth of Drosophila's genetic tools offers the possibility to study motor control at single-neuron resolution, and soon throughout entire circuits. As an entry to these circuits, we provide detailed anatomy of proboscis motor neurons, muscles, and joints. We create a collection of fly strains to individually manipulate every proboscis muscle through control of its motor neurons, the first such collection for an appendage. We generate a model of the action of each proboscis joint, and find that only a small number of motor neurons are needed to produce proboscis reaching. Comprehensive control of each motor element in this numerically simple system paves the way for future study of both reflexive and flexible movements of this appendage.

Spiders are important predators in terrestrial ecosystems, yet we know very little about the principal feeding structures of spiders, the chelicerae, which are functionally equivalent to "jaws" or "mandibles" and are an extremely important aspect of spider biology. In particular, members of Palpimanoidea have evolved highly unusual cheliceral morphologies and functions, including high-speed, ballistic movements in mecysmaucheniid spiders, the fastest arachnid movements known thus far, and the elongated, highly maneuverable chelicerae of archaeids that use an attack-at-a-distance strategy. Here, using micro-Computed-Tomography scanning techniques, we perform a comparative study to examine cheliceral muscle morphology in six different spider specimens representing five palpimanoid families. We provide a hypothesis for homology in palpimanoid cheliceral muscles and then compare and contrast these findings with previous studies on other non-palpimanoid spiders. We document and discuss two sets of cheliceral muscles in palpimanoids that have not been previously observed in other spiders or which may represent a position shift compared to other spiders. In the palpimanoids, Palpimanus sp., Huttonia sp., and Colopea sp. showed similar cheliceral muscle anatomy. In Eriauchenius ranavalona, which has highly maneuverable chelicerae, some of the muscles have a more horizontal orientation, and there is a greater degree of cheliceral muscle divergence. In Zearchaea sp. and Aotearoa magna, some muscles have also shifted to a more horizontal orientation, and in Zearchaea sp., a species with a ballistic, high-speed predatory strike, there is a loss of cheliceral muscles. This research is a first step toward understanding cheliceral form and function across spiders.

Despite the importance of pelvic floor muscles, significant controversy still exists about the true structural details of these muscles. We provide an objective analysis of the architecture and orientation of the superficial muscles of the perineum using a novel approach. Magnetic Resonance Diffusion Tensor Images (MR-DTI) were acquired in 10 healthy asymptomatic nulliparous women, and 4 healthy males. Global tractography was then used to generate the architecture of the muscles. Micro-CT imaging of a male cadaver was performed for validation of the fiber tracking results. Results show that muscles fibers of the external anal sphincter, from the right and left side, cross midline in the region of the perineal body to continue as transverse perinea and bulbospongiosus muscles of the opposite side. The morphology of the external anal sphincter resembles that of the number '8' or a "purse string". The crossing of muscle fascicles in the perineal body was supported by micro-CT imaging in the male subject. The superficial muscles of the perineum, and external anal sphincter are frequently damaged during child birth related injuries to the pelvic floor; we propose the use of MR-DTI based global tractography as a non-invasive imaging technique to assess damage to these muscles.

Purpose: Most bladder cancers are early-stage tumors known as papillary non-muscle-invasive bladder cancer (NMIBC). After resection, up to 70% of NMIBCs recur locally, and up to 20% of these recurrences progress to muscle invasion. There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. We previously identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence in a pilot cohort that STAG2-mutant tumors recurred less frequently than STAG2 wild-type tumors. Here, we report a STAG2 biomarker validation study using two independent cohorts of clinically annotated papillary NMIBC tumors from the United States and Europe.Experimental Design: The value of STAG2 immunostaining for prediction of recurrence was initially evaluated in a cohort of 82 patients with papillary NMIBC ("Georgetown cohort"). Next, the value of STAG2 immunostaining for prediction of progression to muscle invasion was evaluated in a progressor-enriched cohort of 253 patients with papillary NMIBC ("Aarhus cohort").Results: In the Georgetown cohort, 52% of NMIBC tumors with intact STAG2 expression recurred, whereas 25% of STAG2-deficient tumors recurred (P = 0.02). Multivariable analysis identified intact STAG2 expression as an independent predictor of recurrence (HR = 2.4; P = 0.05). In the progressor-enriched Aarhus cohort, 38% of tumors with intact STAG2 expression progressed within 5 years, versus 16% of STAG2-deficient tumors (P < 0.01). Multivariable analysis identified intact STAG2 expression as an independent predictor of progression (HR = 1.86; P = 0.05).Conclusions: STAG2 IHC is a simple, binary, new assay for risk stratification in papillary NMIBC. Clin Cancer Res; 24(17); 4145-53. ©2018 AACR.

Large fluctuations in animal body mass in relation to life-history events can influence contaminant concentrations and toxicological risk. We quantified mercury concentrations in adult northern elephant seals (Mirounga angustirostris) before and after lengthy at sea foraging trips (n = 89) or fasting periods on land (n = 27), and showed that mercury concentrations in blood and muscle changed in response to these events. The highest blood mercury concentrations were observed after the breeding fast, whereas the highest muscle mercury concentrations were observed when seals returned to land to moult. Mean female blood mercury concentrations decreased by 30% across each of the two annual foraging trips, demonstrating a foraging-associated dilution of mercury concentrations as seals gained mass. Blood mercury concentrations increased by 103% and 24% across the breeding and moulting fasts, respectively, demonstrating a fasting-associated concentration of mercury as seals lost mass. In contrast to blood, mercury concentrations in female's muscle increased by 19% during the post-breeding foraging trip and did not change during the post-moulting foraging trip. While fasting, female muscle mercury concentrations increased 26% during breeding, but decreased 14% during moulting. Consequently, regardless of exposure, an animal's contaminant concentration can be markedly influenced by their annual life-history events.

Cell populations display heterogeneous and dynamic phenotypic states at multiple scales. Similar to molecular features commonly used to explore cell heterogeneity, cell behavior is a rich phenotypic space that may allow for identification of relevant cell states. Inference of cell state from cell behavior across a time course may enable the investigation of dynamics of transitions between heterogeneous cell states, a task difficult to perform with destructive molecular observations. Cell motility is one such easily observed cell behavior with known biomedical relevance. To investigate heterogenous cell states and their dynamics through the lens of cell behavior, we developed Heteromotility, a software tool to extract quantitative motility features from timelapse cell images. In mouse embryonic fibroblasts (MEFs), myoblasts, and muscle stem cells (MuSCs), Heteromotility analysis identifies multiple motility phenotypes within the population. In all three systems, the motility state identity of individual cells is dynamic. Quantification of state transitions reveals that MuSCs undergoing activation transition through progressive motility states toward the myoblast phenotype. Transition rates during MuSC activation suggest non-linear kinetics. By probability flux analysis, we find that this MuSC motility state system breaks detailed balance, while the MEF and myoblast systems do not. Balanced behavior state transitions can be captured by equilibrium formalisms, while unbalanced switching between states violates equilibrium conditions and would require an external driving force. Our data indicate that the system regulating cell behavior can be decomposed into a set of attractor states which depend on the identity of the cell, together with a set of transitions between states. These results support a conceptual view of cell populations as dynamical systems, responding to inputs from signaling pathways and generating outputs in the form of state transitions and observable motile behaviors.

BackgroundThe tropical gar (Atractosteus tropicus) is the southernmost species of the seven extant species of gar fishes in the world. In Mexico and Central America, the species is an important food source due to its nutritional quality and low price. Despite its regional importance and increasing concerns about overexploitation and habitat degradation, basic genetic information on the tropical gar is lacking. Determining genetic information on the tropical gar is important for the sustainable management of wild populations, implementation of best practices in aquaculture settings, evolutionary studies of ancient lineages, and an understanding of sex-specific gene expression. In this study, the transcriptome of the tropical gar was sequenced and assembled de novo using tissues from three males and three females using Illumina sequencing technology. Sex-specific and highly differentially expressed transcripts in brain and muscle tissues between adult males and females were subsequently identified.ResultsThe transcriptome was assembled de novo resulting in 80,611 transcripts with a contig N50 of 3,355 base pairs and over 168 kilobases in total length. Male muscle, brain, and gonad as well as female muscle and brain were included in the assembly. The assembled transcriptome was annotated to identify the putative function of expressed transcripts using Trinotate and SwissProt, a database of well-annotated proteins. The brain and muscle datasets were then aligned to the assembled transcriptome to identify transcripts that were differentially expressed between males and females. The contrast between male and female brain identified 109 transcripts from 106 genes that were significantly differentially expressed. In the muscle comparison, 82 transcripts from 80 genes were identified with evidence for significant differential expression. Almost all genes identified as differentially expressed were sex-specific. The differentially expressed transcripts were enriched for genes involved in cellular functioning, signaling, immune response, and tissue-specific functions.ConclusionsThis study identified differentially expressed transcripts between male and female gar in muscle and brain tissue. The majority of differentially expressed transcripts had sex-specific expression. Expanding on these findings to other developmental stages, populations, and species may lead to the identification of genetic factors contributing to the skewed sex ratio seen in the tropical gar and of sex-specific differences in expression in other species. Finally, the transcriptome assembly will open future research avenues on tropical gar development, cell function, environmental resistance, and evolution in the context of other early vertebrates.

PurposeWe present three-dimensional adiabatic inversion recovery prepared ultrashort echo time Cones (3D IR-UTE-Cones) imaging of cortical bone in the hip of healthy volunteers using a clinical 3T scanner.MethodsA 3D IR-UTE-Cones sequence, based on a short pulse excitation followed by a 3D Cones trajectory, with a nominal TE of 32μs, was employed for high contrast morphological imaging of cortical bone in the hip of heathy volunteers. Signals from soft tissues such as muscle and marrow fat were suppressed via adiabatic inversion and signal nulling. T2⁎ value of the cortical bone was also calculated based on 3D IR-UTE-Cones acquisitions with a series of TEs ranging from 0.032 to 0.8ms. A total of four healthy volunteers were recruited for this study. Average T2⁎ values and the standard deviation for four regions of interests (ROIs) at the greater trochanter, the femoral neck, the femoral head and the lesser trochanter were calculated.ResultsThe 3D IR-UTE-Cones sequence provided efficient suppression of soft tissues with excellent image contrast for cortical bone visualization in all volunteer hips. Exponential single component decay was observed for all ROIs, with averaged T2⁎ values ranging from 0.33 to 0.45ms, largely consistent with previously reported T2⁎ values of cortical bone in the tibial midshaft.ConclusionsThe 3D IR-UTE-Cones sequence allows in vivo volumetric imaging and quantitative T2⁎ measurement of cortical bone in the hip using a clinical 3T scanner.

Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

Study designProspective case series.ObjectiveEvaluate lumbar paraspinal muscle (PSM) cross-sectional area and intervertebral disc (IVD) height changes induced by a 6-month space mission on the International Space Station. The long-term objective of this project is to promote spine health and prevent spinal injury during space missions and here on Earth.Summary of background dataNational Aeronautics and Space Administration (NASA) crewmembers have a 4.3 times higher risk of herniated IVDs, compared with the general and military aviator populations. The highest risk occurs during the first year after a mission. Microgravity exposure during long-duration spaceflights results in approximately 5 cm lengthening of body height, spinal pain, and skeletal deconditioning. How the PSMs and IVDs respond during spaceflight is not well described.MethodsSix NASA crewmembers were imaged supine with a 3 Tesla magnetic resonance imaging. Imaging was conducted preflight, immediately postflight, and then 33 to 67 days after landing. Functional cross-sectional area (FCSA) measurements of the PSMs were performed at the L3-4 level. FCSA was measured by grayscale thresholding within the posterior lumbar extensors to isolate lean muscle on T2-weighted scans. IVD heights were measured at the anterior, middle, and posterior sections of all lumbar levels. Repeated measures analysis of variance was used to determine significance at P

BACKGROUND/AIMS: Graded vertical rectus tenotomy (GVRT) is postulated as effective for small-angle vertical heterotropia. We aimed to determine the dosing recommendations for GVRT in sagging eye syndrome (SES). METHODS: This was a retrospective, observational study of surgical outcomes for GVRT from 2009 to 2014 in a single surgeons academic practice. There were 37 (20 women) patients of average age 68±10 (SD) years with comitant or incomitant hypertropia ≤10Δ caused by SES. The main outcome measure was the dose-effect of GVRT required to correct intraoperative hypertropia. RESULTS: Preoperative average central gaze hypertropia measured 4.7±2.2Δ. Three patients underwent repeat GVRT for residual or consecutive hypertropia, one undergoing it twice. All surgeries were analysed, increasing the total operations to 41. The inferior rectus tendon in the hypotropic eye was operated in 32 eyes, and the superior rectus tendon in the hypertropic eye in 9 eyes. Mean tenotomy was 68±19% of tendon width. Hypertropia was always eliminated intraoperatively by progressive GVRT. Mean hypertropia was 1.1±1.6Δ at average 93 days postoperatively. Linear regression demonstrated that 3-6Δ hypertropia correction requires 30%-90% graded tenotomy (R(2)=0.32, p

Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.

BackgroundThe absence of a discrete mass, surrounding signal abnormality and solid enhancement are imaging features that have traditionally been used to differentiate soft-tissue arteriovenous malformations from vascular tumors on MRI. We have observed that these findings are not uncommon in arteriovenous malformations, which may lead to misdiagnosis or inappropriate treatment.ObjectiveTo estimate the frequency of atypical MRI features in soft-tissue arteriovenous malformations and assess their relationship to lesion size, location, tissue type involved and vascular architecture.Materials and methodsMedical records, MRI and histopathology were reviewed in consecutive patients with soft-tissue arteriovenous malformations in a multidisciplinary vascular anomalies clinic. Arteriovenous malformations were divided into those with and without atypical MRI findings (perilesional T2 signal abnormality, enhancement and/or a soft-tissue mass). Lesion location, size, tissue involved and vascular architecture were also compared between groups. Tissue stains were reviewed in available biopsy or resection specimens to assess relationships between MRI findings and histopathology.ResultsThirty patients with treatment-naïve arteriovenous malformations were included. Fifteen lesions demonstrated atypical MRI. There was no difference in age, gender, lesion size or involved body part between the groups. However, more than half of the atypical lesions demonstrated multicompartmental involvement, and tiny intralesional flow voids were more common in atypical arteriovenous malformations. Histopathology also differed in atypical cases, showing densely packed endothelial cells with connective tissue architectural distortion and edema.ConclusionArteriovenous malformations may exhibit features of a vascular tumor on MRI, particularly when multicompartmental and/or containing tiny internal vessels. These features are important to consider in suspected fast-flow vascular malformations and may have implications with respect to their treatment.

The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. The basis for pathogenesis is unknown. To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, we found morphological abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, we identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem-cell-derived neurons from patients with C9orf72-related disease. These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.

The human body has been shaped by natural selection during the past 4-5 million years. Fossils preserve bones and teeth but lack muscle, skin, fat, and organs. To understand the evolution of the human form, information about both soft and hard tissues of our ancestors is needed. Our closest living relatives of the genus Pan provide the best comparative model to those ancestors. Here, we present data on the body composition of 13 bonobos (Pan paniscus) measured during anatomical dissections and compare the data with Homo sapiens. These comparative data suggest that both females and males (i) increased body fat, (ii) decreased relative muscle mass, (iii) redistributed muscle mass to lower limbs, and (iv) decreased relative mass of skin during human evolution. Comparison of soft tissues between Pan and Homo provides new insights into the function and evolution of body composition.

BACKGROUND: Plication is an alternative tightening procedure to resection. In monkeys, plication has been shown to preserve anterior segment circulation compared with full-tendon tenotomy, but this is unconfirmed in humans. PURPOSE: To evaluate anterior segment circulation by iris angiography before and after strabismus surgery in humans. METHODS: Prospective, blinded study of 14 patients (mean age (SD), 58.6 (14.3)) undergoing plication and/or full tendon tenotomy (resection or recession) from August 2013 to March 2014. Eight patients (mean age (SD), 59.0 (13.3)) underwent plication of one muscle with or without recession of a second muscle on the same eye and six patients (mean age (SD), 58.2 (16.8)) underwent tenotomy of one to two muscles on the same eye. Preoperative and postoperative iris angiograms were compared for changes in perfusion by a masked examiner. In patients undergoing binocular surgery, one eye was chosen preoperatively to be the study eye. RESULTS: Postoperative iris filling defects were present in four patients (67%) after tenotomy and one patient (12.5%) after plication (p=0.09). Of the seven total vertical rectus muscles operated (three tenotomies and four plications), filling defects were present after three tenotomies and one plication (100% vs 25%; p=0.14). Of the 13 total horizontal rectus muscles operated (eight tenotomies and five plications), filling defects were present after one tenotomy and none of the plications (13% vs 0%; p=0.99). CONCLUSIONS: Rectus muscle plication spares the ciliary vessels and may be considered a safer alternative to resection for patients at risk for anterior segment ischaemia, especially when surgery involves a vertical rectus muscle.

The tumour suppressor Merlin, encoded by the gene NF2, is frequently mutated in the autosomal dominant disorder neurofibromatosis type II, characterised primarily by the development of schwannoma and other glial cell tumours. However, NF2 is expressed in virtually all analysed human and rodent organs, and its deletion in mice causes early embryonic lethality. Additionally, NF2 encodes for two major isoforms of Merlin of unknown functionality. Specifically, the tumour suppressor potential of isoform 2 remains controversial. In this study, we used Nf2 isoform-specific knockout mouse models to analyse the function of each isoform during development and organ homeostasis. We found that both isoforms carry full tumour suppressor functionality and can completely compensate the loss of the other isoform during development and in most adult organs. Surprisingly, we discovered that spermatogenesis is strictly dependent on the presence of both isoforms. While the testis primarily expresses isoform 1, we noticed an enrichment of isoform 2 in spermatogonial stem cells. Deletion of either isoform was found to cause decreased sperm quality as observed by maturation defects and head/midpiece abnormalities. These defects led to impaired sperm functionality as assessed by decreased sperm capacitation. Thus, we describe spermatogenesis as a new Nf2-dependent process. Additionally, we provide for the first time in vivo evidence for equal tumour suppressor potentials of Merlin isoform 1 and isoform 2.

Understanding the skeletal effects of resistance exercise involves delineating the spatially heterogeneous response of bone to load distributions from different muscle contractions. Bone mineral density (BMD) analyses may obscure these patterns by averaging data from tissues with variable mechanoresponse. To assess the proximal femoral response to resistance exercise, we acquired pretraining and posttraining quantitative computed tomography (QCT) images in 22 subjects (25-55 years, 9 males, 13 females) performing two resistance exercises for 16 weeks. One group (SQDL, n = 7) performed 4 sets each of squats and deadlifts, a second group (ABADD, n = 8) performed 4 sets each of standing hip abductions and adductions, and a third group (COMBO, n = 7) performed two sets each of squat/deadlift and abduction/adduction exercise. Subjects exercised three times weekly, and the load was adjusted each session to maximum effort. We used voxel-based morphometry (VBM) to visualize BMD distributions. Hip strength computations used finite element modeling (FEM) with stance and fall loading conditions. We used QCT analysis for cortical and trabecular BMD, and cortical tissue volume. For muscle size and density, we analyzed the cross-sectional area (CSA) and mean Hounsfield unit (HU) in the hip extensor, flexor, abductor, and adductor muscle groups. Whereas SQDL increased vertebral BMD, femoral neck cortical BMD and volume, and stance hip strength, ABADD increased trochanteric cortical volume. The COMBO group showed no changes in any parameter. VBM showed different effects of ABADD and SQDL exercise, with the former causing focal changes of trochanteric cortical bone, and the latter showing diffuse changes in the femoral neck and head. ABADD exercise increased adductor CSA and HU, whereas SQDL exercise increased the hip extensor CSA and HU. In conclusion, we observed different proximal femoral bone and muscle tissue responses to SQDL and ABADD exercise. This study supports VBM and volumetric QCT (vQCT) to quantify the spatially heterogeneous effects of types of muscle contractions on bone.

Study objectivesThe effect of common sedatives on upper airway physiology and breathing during sleep in obstructive sleep apnea (OSA) has been minimally studied. Conceptually, certain sedatives may worsen OSA in some patients. However, sleep and breathing could improve with certain sedatives in patients with OSA with a low respiratory arousal threshold. This study aimed to test the hypothesis that trazodone increases the respiratory arousal threshold in patients with OSA and a low arousal threshold. Secondary aims were to examine the effects of trazodone on upper airway dilator muscle activity, upper airway collapsibility, and breathing during sleep.DesignPatients were studied on 4 separate nights according to a within-subjects cross-over design.SettingSleep physiology laboratory.PatientsSeven patients with OSA and a low respiratory arousal threshold.InterventionsIn-laboratory polysomnograms were obtained at baseline and after 100 mg of trazodone was administered, followed by detailed overnight physiology experiments under the same conditions. During physiology studies, continuous positive airway pressure was transiently lowered to measure arousal threshold (negative epiglottic pressure prior to arousal), dilator muscle activity (genioglossus and tensor palatini), and upper airway collapsibility (Pcrit).Measurements and resultsTrazodone increased the respiratory arousal threshold by 32 ± 6% (-11.5 ± 1.4 versus -15.3 ± 2.2 cmH2O, P < 0.01) but did not alter the apnea-hypopnea index (39 ± 12 versus 39 ± 11 events/h sleep, P = 0.94). Dilator muscle activity and Pcrit also did not systematically change with trazodone.ConclusionsTrazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold without major impairment in dilator muscle activity or upper airway collapsibility. However, the magnitude of change in arousal threshold was insufficient to overcome the compromised upper airway anatomy in these patients.

BACKGROUND: Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy of the elderly that does not show significant clinical improvement in response to steroid therapy. Distinguishing IBM from polymyositis (PM) is clinically important since PM is steroid-responsive; however, the two conditions can show substantial histologic overlap. RESULTS: We performed quantitative immunohistochemistry for (1) autophagic markers LC3 and p62 and (2) protein aggregation marker TDP-43 in 53 subjects with pathologically diagnosed PM, IBM, and two intermediate T cell-mediated inflammatory myopathies (polymyositis with COX-negative fibers and possible IBM). The percentage of stained fibers was significantly higher in IBM than PM for all three immunostains, but the markers varied in sensitivity and specificity. In particular, both LC3 and p62 were sensitive markers of IBM, but the tradeoff between sensitivity and specificity was smaller (and diagnostic utility thus greater) for LC3 than for p62. In contrast, TDP-43 immunopositivity was highly specific for IBM, but the sensitivity of this test was low, with definitive staining present in just 67% of IBM cases. CONCLUSIONS: To differentiate IBM from PM, we thus recommend using a panel of LC3 and TDP-43 antibodies: the finding of 7% of TDP-43-positive fibers strongly supports a diagnosis of IBM. These data provide support for the hypothesis that disruption of autophagy and protein aggregation contribute to IBM pathogenesis.

In hemodialysis patients, lower body mass index and weight loss have been associated with higher mortality rates, a phenomenon sometimes called the obesity paradox. This apparent paradox might be explained by loss of muscle mass. The authors thus examined the relation to mortality of changes in dry weight and changes in serum creatinine levels (a muscle-mass surrogate) in a cohort of 121,762 hemodialysis patients who were followed for up to 5 years (2001-2006). In addition to conventional regression analyses, the authors conducted a ranking analysis of joint effects in which the sums and differences of the percentiles of change for the 2 measures in each patient were used as the regressors. Concordant with previous body mass index observations, lower body mass, lower muscle mass, weight loss, and serum creatinine decline were associated with higher death rates. Among patients with a discordant change, persons whose weight declined but whose serum creatinine levels increased had lower death rates than did those whose weight increased but whose serum creatinine level declined. A decline in serum creatinine appeared to be a stronger predictor of mortality than did weight loss. Assuming residual selection bias and confounding were not large, the present results suggest that a considerable proportion of the obesity paradox in dialysis patients might be explained by the amount of decline in muscle mass.

The evolutionary fate of an allele ordinarily depends on its contribution to host fitness. Occasionally, however, genetic elements arise that are able to gain a transmission advantage while simultaneously imposing a fitness cost on their hosts. We previously discovered one such element in C. elegans that gains a transmission advantage through a combination of paternal-effect killing and zygotic self-rescue. Here we demonstrate that this element is composed of a sperm-delivered toxin, peel-1, and an embryo-expressed antidote, zeel-1. peel-1 and zeel-1 are located adjacent to one another in the genome and co-occur in an insertion/deletion polymorphism. peel-1 encodes a novel four-pass transmembrane protein that is expressed in sperm and delivered to the embryo via specialized, sperm-specific vesicles. In the absence of zeel-1, sperm-delivered PEEL-1 causes lethal defects in muscle and epidermal tissue at the 2-fold stage of embryogenesis. zeel-1 is expressed transiently in the embryo and encodes a novel six-pass transmembrane domain fused to a domain with sequence similarity to zyg-11, a substrate-recognition subunit of an E3 ubiquitin ligase. zeel-1 appears to have arisen recently, during an expansion of the zyg-11 family, and the transmembrane domain of zeel-1 is required and partially sufficient for antidote activity. Although PEEL-1 and ZEEL-1 normally function in embryos, these proteins can act at other stages as well. When expressed ectopically in adults, PEEL-1 kills a variety of cell types, and ectopic expression of ZEEL-1 rescues these effects. Our results demonstrate that the tight physical linkage between two novel transmembrane proteins has facilitated their co-evolution into an element capable of promoting its own transmission to the detriment of organisms carrying it.

PurposeTo investigate the mechanisms underpinning modifications in glucose homeostasis and insulin sensitivity 24 h after a bout of resistance exercise (RE) with or without protein ingestion.MethodsTwenty-four healthy males were assigned to a control (CON; n = 8), exercise (EX; n = 8) or exercise plus protein condition (EX+PRO; n = 8). Muscle biopsy and blood samples were obtained at rest for all groups and immediately post-RE (75% 1RM, 8×10 repetitions of leg-press and extension exercise) for EX and EX+PRO only. At 24 h post-RE (or post-resting biopsy for CON), a further muscle biopsy was obtained. Participants then consumed an oral glucose load (OGTT) containing 2 g of [U-¹³C] glucose during an infusion of 6, 6-[²H₂] glucose. Blood samples were obtained every 10 min for 2 h to determine glucose kinetics. EX+PRO ingested an additional 25 g of intact whey protein with the OGTT. A final biopsy sample was obtained at the end of the OGTT.ResultsFasted plasma glucose and insulin were similar for all groups and were not different immediately post- and 24 h post-RE. Following RE, muscle glycogen was 26±8 and 19±6% lower in EX and EX+PRO, respectively. During OGTT, plasma glucose AUC was lower for EX and EX+PRO (75.1±2.7 and 75.3±2.8 mmol·L⁻¹∶120 min, respectively) compared with CON (90.6±4.1 mmol·L⁻¹∶120 min). Plasma insulin response was 13±2 and 21±4% lower for EX and CON, respectively, compared with EX+PRO. Glucose disappearance from the circulation was ∼12% greater in EX and EX+PRO compared with CON. Basal 24 h post-RE and insulin-stimulated PAS-AS160/TBC1D4 phosphorylation was greater for EX and EX+PRO.ConclusionsPrior RE improves glycemic control and insulin sensitivity through an increase in the rate at which glucose is disposed from the circulation. However, co-ingesting protein during a high-glucose load does not augment this response at 24 h post-exercise in healthy, insulin-sensitive individuals.

BackgroundMitochondrial dysfunction and oxidative stress are central mechanisms underlying the aging process and the pathogenesis of many age-related diseases. Selected antioxidants and specific combinations of nutritional compounds could target many biochemical pathways that affect both oxidative stress and mitochondrial function and, thereby, preserve or enhance physical performance.Methodology/principal findingsIn this study, we evaluated the potential anti-aging benefits of a Q-ter based nutritional mixture (commercially known as Eufortyn) mainly containing the following compounds: terclatrated coenzyme Q(10) (Q-ter), creatine and a standardized ginseng extract. We found that Eufortyn supplementation significantly ameliorated the age-associated decreases in grip strength and gastrocnemius subsarcolemmal mitochondria Ca(2+) retention capacity when initiated in male Fischer344 x Brown Norway rats at 21 months, but not 29 months, of age. Moreover, the increases in muscle RNA oxidation and subsarcolemmal mitochondrial protein carbonyl levels, as well as the decline of total urine antioxidant power, which develop late in life, were mitigated by Eufortyn supplementation in rats at 29 months of age.Conclusions/significanceThese data imply that Eufortyn is efficacious in reducing oxidative damage, improving the age-related mitochondrial functional decline, and preserving physical performance when initiated in animals at early midlife (21 months). The efficacy varied, however, according to the age at which the supplementation was provided, as initiation in late middle age (29 months) was incapable of restoring grip strength and mitochondrial function. Therefore, the Eufortyn supplementation may be particularly beneficial when initiated prior to major biological and functional declines that appear to occur with advancing age.