GCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression.

Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5skm-/-) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.

Sodium Ingestion Improves Groundstroke Performance in Nationally-Ranked Tennis Players: A Randomized, Placebo-Controlled Crossover Trial.

This study examined the dose-response effects of ingesting different sodium concentrations on markers of hydration and tennis skill. Twelve British nationally-ranked tennis players (age: 21.5 ± 3.1 years; VO2peak: 45.5 ± 4.4 ml.kg.min-1) completed four identical in-door tennis training sessions in a cluster randomized, single-blind, placebo-controlled, crossover design. Twenty-minutes prior to each training session, participants consumed a 250 ml sodium-containing beverage (10, 20, 50 mmol/L) or a placebo (0 mmol/L), and continued to consume 1,000 ml of the same beverage at set periods during the 1-h training session. Tennis groundstroke and serve performance, agility, urine osmolality, fluid loss, sodium sweat loss and perceptual responses (rating of perceived exertion (RPE), thirst, and gastrointestinal (GI) discomfort) were assessed. Results showed that ingesting 50 mmol/L sodium reduced urine osmolality (-119 mOsmol/kg; p = 0.037) and improved groundstroke performance (5.4; p < 0.001) compared with placebo. This was associated with a reduction in RPE (-0.42; p = 0.029), perception of thirst (-0.58; p = 0.012), and GI discomfort (-0.55; p = 0.019) during the 50 mmol/L trial compared with placebo. Linear trend analysis showed that ingesting greater concentrations of sodium proportionately reduced urine osmolality (ß = -147 mOsmol/kg; p = 0.007) and improved groundstroke performance (ß = 5.6; p < 0.001) in a dose response manner. Perceived thirst also decreased linearly as sodium concentration increased (ß = -0.51; p = 0.044). There was no evidence for an effect of sodium consumption on fluid loss, sweat sodium loss, serve or agility performance (p > 0.05). In conclusion, consuming 50 mmol/L of sodium before and during a 1-h tennis training session reduced urine osmolality and improved groundstroke performance in nationally-ranked tennis players. There was also evidence of dose response effects, showing that ingesting greater sodium concentrations resulted in greater improvements in groundstroke performance. The enhancement in tennis skill may have resulted from an attenuation of symptomologic distracters associated with hypohydration, such as RPE, thirst and GI discomfort.

Feasibility of a novel exercise prehabilitation programme in patients scheduled for elective colorectal surgery: a feasibility randomised controlled trial.

BACKGROUND AND OBJECTIVES: To investigate the feasibility of delivering a functional exercise-based prehabilitation intervention and its effects on postoperative length of hospital stay, preoperative physical functioning and health-related quality of life in elective colorectal surgery. MATERIALS AND METHODS: In this randomised controlled feasibility trial, 22 elective colorectal surgery patients were randomly assigned to exercise prehabilitation (n = 11) or standard care (n = 11). Feasibility of delivering the intervention was assessed based on recruitment and compliance to the intervention. Impact on postoperative length of hospital stay and complications, preoperative physical functioning (timed up and go test, five times sit to stand, stair climb test, handgrip dynamometry and 6-min walk test) and health-related quality of life were also assessed. RESULTS: Over 42% of patients (84/198) screened were deemed ineligible for prehabilitation due to insufficient time existing prior to scheduled surgery. Of those who were eligible, approximately 18% consented to the trial. Median length of hospital stay was 8 [range 6-27] and 10 [range 5-12] days respectively for the standard care and prehabilitation groups. Patterns towards preoperative improvements for the timed up and go test, stair climb test and 6-min walk test were observed for all participants receiving prehabilitation but not standard care. CONCLUSIONS: Despite prehabilitation appearing to convey positive benefits on physical functioning, short surgical wait times and patient engagement represent major obstacles to implementing exercise prehabilitation programmes in colorectal cancer patients.

When Helping Hurts: Nonabusing Family, Friends, and Neighbors in the Lives of Elder Mistreatment Victims.

Purpose of the Study: Elder mistreatment is an epidemic with significant consequences to victims. Little is known, however, about another affected group: nonabusing family members, friends, and neighbors in the lives of the older victim or "concerned persons." This study aimed to identify (a) the prevalence of adults aged 18 and older who have encountered an elder mistreatment situation, (b) the proportion of these who helped the elder victim, and (c) the subjective levels of distress experienced by respondents who helped the victim versus those who did not. Design and Methods: Data were collected from a nationally representative telephone survey of 1,000 adults (18+). Multiple linear regression was used to test the relationship between "helping status" and personal distress attributed to an elder mistreatment, defined as someone aged 60 and older experiencing violence, psychological abuse, financial exploitation, or neglect by a caregiver. Results: Nearly 30% of adults knew a relative, friend, or neighbor who experienced elder mistreatment. Of these, 67% reported personal distress resulting from the mistreatment at a level of 8 or more out of 10. Assuming a helping role was associated with significantly higher levels of personal distress. Greater distress was also associated with being a woman, increasing age, and lower household income. Implications: Knowing about an elder mistreatment situation is highly distressing for millions of adults in the United States, particularly for those assuming a helping role. We suggest intervention approaches and future research to better understand the role and needs of concerned persons.

Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies.

Glutaredoxin 2 (GRX2), a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC) to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies.

Fast automated analysis of strong gravitational lenses with convolutional neural networks.

Quantifying image distortions caused by strong gravitational lensing-the formation of multiple images of distant sources due to the deflection of their light by the gravity of intervening structures-and estimating the corresponding matter distribution of these structures (the 'gravitational lens') has primarily been performed using maximum likelihood modelling of observations. This procedure is typically time- and resource-consuming, requiring sophisticated lensing codes, several data preparation steps, and finding the maximum likelihood model parameters in a computationally expensive process with downhill optimizers. Accurate analysis of a single gravitational lens can take up to a few weeks and requires expert knowledge of the physical processes and methods involved. Tens of thousands of new lenses are expected to be discovered with the upcoming generation of ground and space surveys. Here we report the use of deep convolutional neural networks to estimate lensing parameters in an extremely fast and automated way, circumventing the difficulties that are faced by maximum likelihood methods. We also show that the removal of lens light can be made fast and automated using independent component analysis of multi-filter imaging data. Our networks can recover the parameters of the 'singular isothermal ellipsoid' density profile, which is commonly used to model strong lensing systems, with an accuracy comparable to the uncertainties of sophisticated models but about ten million times faster: 100 systems in approximately one second on a single graphics processing unit. These networks can provide a way for non-experts to obtain estimates of lensing parameters for large samples of data.

NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.

Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD+) synthesis, consistent with a potential role for the essential cofactor NAD+ in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD+ and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD+ levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis. Replenishing NAD+ stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr-/- mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD+ repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD+ may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures.

Effect of osteoarthritis on accuracy of continuous tracking leg movement.

The purpose of this study was to establish if osteoarthritis in older adults was associated with ability to accurately and continuously track leg movement in a model of therapy to improve age-related impairments of proprioception, kinesthesia, and coordination of muscles at the knee joint. 24 older adults without osteoarthritis and 24 older adults with osteoarthritis participated. Software generated a moving, on-screen sine wave and a vertically traveling disc. Participants attempted to keep the disc on the sine wave by bending and straightening the leg. Older adults without osteoarthritis performed better than older adults with osteoarthritis in one of two conditions. There was a relationship between osteoarthritis and reduced accuracy of leg movement. Further research will be required to specifically define this relationship and to establish if such interventions to improve accuracy of knee movement will positively affect functional capabilities of individuals with osteoarthritis.

Effects of age and task characteristics on continuous motor tracking performance.

UNLABELLED: BACKGROUND/STUDY CONTEXT: Much has been written regarding age-related changes in sensory and motor functions, general slowing of the nervous system, and deficiencies in inhibition. Few studies, however, have attempted to define how each of these factors may contribute to poorer accuracy of motor performance with aging. The purpose of this study was to examine whether these changes were best explained by speed of task or stimulus-response compatibility. METHODS: Twenty-four younger (M = 19.5; 18-22 years) and older (M = 72.5; 65-82 years) adults used knee movement to track a computer-generated disc along a computer-generated sinusoidal wave that either moved at 50 or 70 cm/s. Stimulus-response compatibility consisted of leg and disc movement in the same direction and stimulus-response incompatibility consisted of leg and disc movement in the opposite direction. Performance was analyzed using a mixed-design analysis of variance (ANOVA). RESULTS: Younger adults performed better than older adults in all conditions. Magnitudes of error between the stimulus-compatible and stimulus-incompatible conditions were greater for the old group compared to the young group. Both of these findings were consistent with the hypotheses. Inconsistent with the hypothesis, speed of task did not contribute to age-related differences in accuracy of motor performance in either cognitive load conditions. CONCLUSION: Differences in performance could be attributed to age-related changes in selective inhibition. Future research should focus on examining the potential consequences of decreased inhibition among older adults when completing various activities of daily living and what interventions might mitigate these consequences.

Motor control of the knee as a function of age and range of motion.

The purpose of this study was to extend the findings of age-related changes in force fluctuation of musculature of the lower extremity by examining whether accuracy of movement differs between young, middle-aged, and older adults depending on the angular position of the lower leg when completing a continuous tracking task. Participants were 24 healthy young adults (17 to 25 years of age), 24 middle-aged adults (40 to 50 years of age), and 24 older adults (65 to 75 years of age). Performance was assessed during active leg flexion and extension movements within end (10 to 40 degrees flexion) and mid (60 to 90 degrees flexion) ranges of knee motion. Older individuals performed more poorly on the motor task, as indicated by a greater mean absolute deviation from the target (mean [M] = 31.96 mm, standard deviation [SD] = 23.83 mm) compared with the young group (M = 10.59 mm, SD = 10.51 mm) and middle-aged group (M = 9.09 mm, SD = 4.55 mm). There was no interaction between age and range of motion. Although clear age-related differences in performance were obtained, there was no evidence that age-related differences in dynamic position sense affected voluntary motor control performance as measured in this study. Whatever factors contribute to age-related changes in motor performance control appear to have consistent affect on performance throughout the range of motion of the knee.

Virus inactivation in a factor VIII/VWF concentrate treated using a solvent/detergent procedure based on polysorbate 20.

Treatment with solvent/detergent is a widely used method for ensuring the virus safety of plasma products. In the present study, virus inactivation by a novel solvent/detergent combination, i.e. TnBP (tri-n-butyl phosphate) and polysorbate 20 during the manufacture of the factor VIII/VWF concentrate Optivate has been investigated. The inactivation of most enveloped viruses was rapid, i.e. > 5 log in 2 min, although the inactivation of vaccinia virus was slower, i.e. 4 log in 1h. Virus inactivation was effective over a wide range of conditions, i.e. solvent/detergent concentration, protein concentration and temperature, irrespective of whether tested individually or in combination. This confirms the effectiveness and robustness of this alternative version of the solvent/detergent procedure, and allows appropriate control limits to be set for this manufacturing step. Polysorbate 20 provides an alternative to the non-ionic detergents currently in use with the solvent/detergent procedure.

The mouse dystrophin muscle promoter/enhancer drives expression of mini-dystrophin in transgenic mdx mice and rescues the dystrophy in these mice.

Successful gene therapy for Duchenne muscular dystrophy (DMD) requires the restoration of dystrophin protein in skeletal muscles. To achieve this goal, appropriate regulatory elements that impart tissue-specific transgene expression need to be identified. Currently, most muscle-directed gene therapy studies utilize the muscle creatine kinase promoter. We have previously described a muscle enhancer element (mDME-1) derived from the mouse dystrophin gene that increases transcription from the mouse dystrophin muscle promoter. Here, we explore the use of this native mouse dystrophin muscle promoter/enhancer to drive expression of a human dystrophin minigene in transgenic mice. We show that the dystrophin promoter can provide tissue-specific transgene expression and that the mini-dystrophin protein is expressed at the sarcolemma of skeletal muscles from mdx mice, where it restores the dystrophin-associated glycoprotein complex. The level of transgene expression obtained is sufficient to protect mdx muscles from the morphological and physiological symptoms of muscular dystrophy, as well as from exercise-induced damage. Therefore, the dystrophin muscle promoter/enhancer sequence represents an alternative for use in gene therapy vectors for the treatment of DMD.

The mouse dystrophin muscle enhancer-1 imparts skeletal muscle, but not cardiac muscle, expression onto the dystrophin Purkinje promoter in transgenic mice.

A subset of patients harboring mutations in the dystrophin gene suffer from X-linked dilated cardiomyopathy (XLCM), a familial heart disease that is not accompanied by any clinical signs of skeletal muscle myopathy. As the muscle (M) isoform of dystrophin is not expressed in these patients, the absence of skeletal muscle symptoms has been attributed to expression of the brain (B) and cerebellar Purkinje (CP) isoforms of dystrophin in skeletal, but not cardiac, muscles of XLCM patients. The compensatory mechanism of dystrophin B and CP promoter upregulation is not known but it has been suggested that the dystrophin muscle enhancer from intron 1, DME-1, may be important in this activity. Previous studies have shown that the presence of the DME-1 is essential for a significant increase in dystrophin B and CP promoter activity in skeletal muscle cells in culture. Here, we demonstrate that the mouse dystrophin CP promoter drives expression of a lacZ reporter gene specifically to the cerebellar Purkinje cell layer but not to skeletal or cardiac muscle of transgenic mice. However, if the mouse counterpart of DME-1 is present in the transgene construct, the dystrophin CP promoter is now activated in skeletal muscle, but not in cardiac muscle. Our findings provide in vivo evidence for the importance of the dystrophin muscle enhancer sequences in activating the dystrophin CP promoter in skeletal muscle. Furthermore, they provide support for the model in which muscle enhancers, like DME-1, activate the dystrophin B and CP promoters in skeletal muscle, but not in cardiac muscle, of XLCM patients.

Dose effects of oral bovine colostrum on physical work capacity in cyclists.

PURPOSE: There is interest in the potential long-term use of dietary supplementation with bovine colostrum to enhance exercise performance. The purpose of the present study was to determine the dose effects of bovine colostrum on cycling performance. METHODS: Forty-two competitive cyclists were randomly divided into three groups and required to consume either 20 g/d bovine colostrum + 40 g whey protein concentrate (wpc), 60 g of bovine colostrum, or 60 g of wpc (placebo). Two measures were used to assess performance before (pre-) and after (post-) an 8-wk supplementation period. The first measure required subjects to complete two VO2max tests separated by 20 min with the amount of work completed in the second test used to evaluate performance. The second performance measure was the time to complete a work-based time trial following a 2-h cycle at 65% VO2max. Subjects were required to maintain their regular training and keep a food and training diary over the study period. RESULTS: After supplementation, the performance enhancement in Measure One was not statistically significantly different in the colostrum groups compared to the placebo group (placebo = 3.4%, 20 g = 4.0%, 60 g = 3.9%; 95% confidence interval (CI) for differences, +/-1.8%, P > 0.05). In performance Measure Two subjects in the 20 g and 60 g groups completed the time trial significantly (P < 0.05) faster post supplement compared to pre supplement (improvements in performance times, placebo = 37 s, 20 g = 158 s, 60 g = 134 s; 95% CI for differences, 47 s). CONCLUSION: Oral bovine colostrum supplementation at 20 g or 60 g/d provided a small but significant improvement in time trial performance in cyclists after a 2-h ride at 65% VO2max.

Mouse dystrophin enhancer preferentially targets lacZ expression in skeletal and cardiac muscle.

Duchenne muscular dystrophy is a muscle wasting disease that results from a dystrophin deficiency in skeletal and cardiac muscle. Studies concerning the regulatory elements that govern dystrophin gene expression in skeletal and/or cardiac muscle in both mouse and human have identified a promoter and an enhancer located in intron 1. In transgenic mice, the muscle promoter alone targets the expression of a lacZ reporter gene only to the right ventricle of the heart, suggesting the need for other regulatory elements to target skeletal muscle and the rest of the heart. Here we report that the mouse dystrophin enhancer from intron 1 can target the expression of a lacZ reporter gene in skeletal muscle as well as in other heart compartments of transgenic mice. Our results also suggest that sequences surrounding the mouse dystrophin enhancer may affect its function throughout mouse development.