ACTN3: More than Just a Gene for Speed.
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ABSTRACT:
SUBMITTER: Pickering C
PROVIDER: S-EPMC5741991 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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Project description:PURPOSE:To examine the effect of ?-actinin-3 deficiency due to homozygosity for the ACTN3 577X-allele on contractile and morphological properties of fast muscle fibers in non-athletic young men. METHODS:A biopsy was taken from the vastus lateralis of 4 RR and 4 XX individuals to test for differences in morphologic and contractile properties of single muscle fibers. The cross-sectional area of the fiber and muscle fiber composition was determined using standard immunohistochemistry analyses. Skinned single muscle fibers were subjected to active tests to determine peak normalized force (P0), maximal unloading velocity (V0) and peak power. A passive stretch test was performed to calculate Young's Modulus and hysteresis to assess fiber visco-elasticity. RESULTS:No differences were found in muscle fiber composition. The cross-sectional area of type IIa and IIx fibers was larger in RR compared to XX individuals (P<0.001). P0 was similar in both groups over all fiber types. A higher V0 was observed in type IIa fibers of RR genotypes (P<0.001) but not in type I fibers. The visco-elasticity as determined by Young's Modulus and hysteresis was unaffected by fiber type or genotype. CONCLUSION:The greater V0 and the larger fast fiber CSA in RR compared to XX genotypes likely contribute to enhanced whole muscle performance during high velocity contractions.
| S-EPMC4773019 | biostudies-literature
Project description:The perceived speed of a ring of equally spaced dots moving around a circular path appears faster as the number of dots increases (Ho & Anstis, 2013, Best Illusion of the Year contest). We measured this "spinner" effect with radial sinusoidal gratings, using a 2AFC procedure where participants selected the faster one between two briefly presented gratings of different spatial frequencies (SFs) rotating at various angular speeds. Compared with the reference stimulus with 4?c/rev (0.64?c/rad), participants consistently overestimated the angular speed for test stimuli of higher radial SFs but underestimated that for a test stimulus of lower radial SFs. The spinner effect increased in magnitude but saturated rapidly as the test radial SF increased. Similar effects were observed with translating linear sinusoidal gratings of different SFs. Our results support the idea that human speed perception is biased by temporal frequency, which physically goes up as SF increases when the speed is held constant. Hence, the more dots or lines, the greater the perceived speed when they are moving coherently in a defined area.
| S-EPMC5435142 | biostudies-other
Project description:Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta-analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3-1.6) but substantial heterogeneity in heterozygotes. In mouse muscle, rAAV-mediated gene transfer overexpressed and rescued ?-actinin-3 expression. Contrary to expectation, in vivo "doping" of ACTN3 at low to moderate doses demonstrated an absence of any change in function. At high doses, ACTN3 is toxic and detrimental to force generation, to demonstrate gene doping with supposedly performance-enhancing isoforms of sarcomeric proteins can be detrimental for muscle function. Restoration of ?-actinin-3 did not enhance muscle mass but highlighted the primary role of ?-actinin-3 in modulating muscle metabolism with altered fatiguability. This is the first study to express a Z-disk protein in healthy skeletal muscle and measure the in vivo effect. The sensitive balance of the sarcomeric proteins and muscle function has relevant implications in areas of gene doping in performance and therapy for neuromuscular disease.
| S-EPMC5986729 | biostudies-literature
Project description: Not available
| S-EPMC9873110 | biostudies-literature
Project description:BACKGROUND:Ability of athletes in speed or endurance contests somehow is determined by inherited muscle fiber types. One of the important genes involved in sport genetics is ACTN3 that is located on chromosome 11q13-q14 and encodes ?-actinin-3, which belongs to highly conserved family of ?-actinin proteins. Genetic analysis of ?-actinin-3 gene has showed a polymorphism R577X (rs1815739), which results in premature stop codon and leads to non functional ?-actnin-3 protein. ACTN3 genotype can contribute to the performance in elite and endurance activities. R577X polymorphism replaces arginine by stop codon. Individuals homozygous for R577 have full copy of ?-actinin-3 and elite and power sprint athletes show significantly higher frequency of 577R allele. In the other hand, some studies represented that X allele have high level of frequency in endurance athletes. However, this data remains controversial Since there is no information about the frequency of ACTN3 genotype in our population therefore as the first step it is essential to determine the genetic background of Iranian population. The objective of this study was to genotype normal Iranian individuals to determine the prevalence of each allele in our population. METHODS:We used PCR-RFLP method for genotyping 210 normal individuals. RESULTS:Total of 210 Iranian normal individuals for distribution of R577X and R alleles were genotyped. The different genotypes were as follow; 24% RR (50/210), 65%RX (136/210) and 11%XX (24/210), with allelic distribution of 0.56 and 0.44 for 577R and 577X alleles of ACTN3. CONCLUSION:This allelic distribution for Iranian's is more close to Caucasian population, which is concurrent with the route of ancient human's migration from Iran Plateau toward Europe. Our results showed no different patterns of allelic distribution among female and males, which was the same in other studies too, although some differences has been reported in the studies on athletes population.
| S-EPMC3518978 | biostudies-literature
Project description:The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.
| S-EPMC5808021 | biostudies-literature
Project description:Cellular immunotherapies promise to transform cancer care. However, they must overcome serious challenges, including: (1) the need to identify and characterize novel cancer antigens to expand the range of therapeutic targets; (2) the need to develop strategies to minimize serious adverse events, such as cytokine release syndrome and treatment-related toxicities; and (3) the need to develop efficient production/manufacturing processes to reduce costs. Here, we discuss whether these challenges might better be addressed through forms of public-private research collaborations, including public-private partnerships (PPPs), or whether these challenges are best addressed by way of standard market transactions. We reviewed 14 public-private relationships and 25 underlying agreements for the clinical development of cancer cellular immunotherapies in the US. Most were based on bilateral research agreements and pure market transactions in the form of service contracts and technology licenses, which is representative of the commercialization focus of the field. We make the strategic case that multiparty PPPs may better advance cancer antigen discovery and characterization and improved cell processing/manufacturing and related activities. In the rush toward the competitive end of the translational continuum for cancer cellular immunotherapy and the attendant focus on commercialization, many gaps have appeared in our understanding of cellular biology, immunology, and bioengineering. We conclude that the model of bilateral agreements between leading research institutions and the private sector may be inadequate to efficiently harness the interdisciplinary skills and knowledge of the public and private sectors to bring these promising therapies to the clinic for the benefit of cancer patients.
| S-EPMC5561330 | biostudies-literature
Project description:Gene drives are selfish genetic elements that are transmitted to progeny at super-Mendelian (>50%) frequencies. Recently developed CRISPR-Cas9-based gene-drive systems are highly efficient in laboratory settings, offering the potential to reduce the prevalence of vector-borne diseases, crop pests and non-native invasive species. However, concerns have been raised regarding the potential unintended impacts of gene-drive systems. This Review summarizes the phenomenal progress in this field, focusing on optimal design features for full-drive elements (drives with linked Cas9 and guide RNA components) that either suppress target mosquito populations or modify them to prevent pathogen transmission, allelic drives for updating genetic elements, mitigating strategies including trans-complementing split-drives and genetic neutralizing elements, and the adaptation of drive technology to other organisms. These scientific advances, combined with ethical and social considerations, will facilitate the transparent and responsible advancement of these technologies towards field implementation.
| S-EPMC8344398 | biostudies-literature
Project description:As human longevity increases, recent research has focused on the maintenance of optimal health during old age. One such area of focus is that of muscle function in the elderly, with a loss of muscle mass increasing the risk of negative outcomes such as sarcopenia and a decrease in bone mineral density. In this mini-review, we focus on the impact of a single nucleotide polymorphism in ACTN3, shown to impact muscle phenotype in elite athletes, on loss of muscle function, maintenance of bone mineral density, and metabolic disorder risk in an elderly population. From the surveyed research, this polymorphism has a clear and demonstrable impact on muscle phenotype and bone mineral density in this population, and acts as a potential modulator for metabolic disorders. As such, knowledge of an individual's ACTN3 genotype may better inform the management of risk factors in the elderly, as well as driving innovations in exercise program design. Subsequently, such insights may contribute to the prolonged maintenance of health and function long into old age.
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Project description:Processing speed is impaired in patients with psychosis, and deteriorates as a function of normal aging. These observations, in combination with other lines of research, suggest that psychosis may be a syndrome of accelerated aging. But do patients with psychosis perform poorly on tasks of processing speed for the same reasons as older adults? Fifty-one patients with psychotic illnesses and 90 controls with similar mean IQ (aged 19-69 years, all African American) completed a computerized processing-speed task, reminiscent of the classic digit-symbol coding task. The data were analyzed using the drift-diffusion model (DDM), and Bayesian inference was used to determine whether psychosis and aging had similar or divergent effects on the DDM parameters. Psychosis and aging were both associated with poor performance, but had divergent effects on the DDM parameters. Patients had lower information-processing efficiency ("drift rate") and longer nondecision time than controls, and psychosis per se did not influence response caution. By contrast, the primary effect of aging was to increase response caution, and had inconsistent effects on drift rate and nondecision time across patients and controls. The results reveal that psychosis and aging influenced performance in different ways, suggesting that the processing-speed impairment in psychosis is more than just accelerated aging. This study also demonstrates the potential utility of computational models and Bayesian inference for finely mapping the contributions of cognitive functions on simple neurocognitive tests.
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