Biology subjects

Johnson, T. E.

Publications and source records attributed to Johnson, T. E..

5 recordsLinked to original sources

bioRxiv2021

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

physiology↗

bioRxiv2021

Effects of TeaCrine(R) (theacrine), Dynamine™ (methylliberine), and caffeine on gamer psychomotor performance in a first-person shooter video game scenario

PurposeTo compare the effects of purported cognitive enhancing dietary bioactive ingredients on subjective and objective measures of cognitive and motor performance during a first-person shooter video game. MethodsUsing a placebo-controlled crossover design, nine healthy men (23.4{+/-}5.7 yr, 178.9{+/-}5.8cm, 86.0{+/-}17.1kg) completed four 20-minute gaming sessions designed to assess cognitive, motor, and perceptual skills via artificial intelligence-driven battery of tasks (Aim Lab). Participants ingested either a placebo (PL), caffeine (CAFF), or caffeine + methylliberine (Dynamine) + theacrine (TeaCrine(R)) (CMT). Before and after each gaming session participants rated various feelings of affect. Data were analyzed using mixed factorial ANOVA, bootstrapping post-hoc tests with 95% confidence intervals, and effect sizes. ResultsCompared to PL, self-assessed performance was significantly increased in CMT vs. PL (p=0.035) and self-assessed jitteriness was increased by CAFF vs. PL (p=0.043). CMT was associated with a greater improvement of participants visuo-spatial working memory from baseline vs. PL (p=0.04) and CAFF (p=0.033). CAFF had a greater decrease in reaction time for false alarms (indicating diminished cognitive control) from baseline vs. PL (p=0.002) and CMT (p=0.001) and a greater increase for time on target tracking vs. PL (p=0.008) and CMT (p=0.047). Compared to PL, CMT was associated with a greater decrease in median kill time (indicating improved speed) (p=0.017). Compared to PL, systolic blood pressure was significantly increased by CAFF (p=0.025) and CMT (p=0.020) but remained within normal limits. ConclusionsAcute CMT supplementation improved cognitive and motor abilities in recreational gamers. The addition of theacrine and methylliberine to caffeine may lessen some undesirable effects of isolated caffeine ingestion on cognitive control and jitteriness.

physiology↗

bioRxiv2019

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency

Diseases that affect the mitochondrial electron transport chain (ETC) often manifest as threshold effect disorders, meaning patients only become symptomatic once a certain level of ETC dysfunction is reached. Multiple processes work to control proximity to the critical ETC threshold and as a consequence there can be significant variability in disease presentation among patients. Identification of such control processes remains an ongoing goal. Checkpoint signaling comprises a collection of alert mechanisms activated in cells in response to nuclear DNA damage. Well-defined hierarchies of proteins are involved in both sensing and signaling DNA damage, with ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) acting as pivotal signaling kinases. In the nematode C. elegans, severe reduction of mitochondrial ETC activity shortens life, as in humans, but mild reduction extends life as a consequence of survival strategies that are invoked under these circumstances. Here we show that removal of ATL-1, the worm ortholog of ATR, unexpectedly lessens the severity of ETC dysfunction, but removal of ATM does not. Multiple genetic and biochemical tests show no evidence for increased mutation or DNA breakage in animals exposed to ETC disruption. Instead, we find that reduced ETC function alters nucleotide ratios within both the ribo- and deoxyribo-nucleotide pools, and causes stalling of RNA polymerase, which is also known to activate ATR. Unexpectedly, atl-1 mutants confronted with mitochondrial ETC disruption maintain normal levels of oxygen consumption and have an increased abundance of translating ribosomes. This suggests checkpoint signaling by ATL-1 normally dampens cytoplasmic translation. Taken together, our data suggests a model whereby ETC insufficiency in C. elegans results in nucleotide imbalances leading to stalling of RNA polymerase, activation of ATL-1, dampening of global translation and magnification of ETC dysfunction. Loss of ATL-1 effectively reverses the severity of ETC disruption so that animals become phenotypically closer to wild type.

pathology↗

bioRxiv2018

Differences in protein dosage underlie nongenetic differences in traits

Phenotypic expression of many traits varies among isogenic individuals in homogeneous environments. Intrinsic variation in the protein chaperone system affects a wide variety of traits in diverse biological systems. In C. elegans, expression of hsp-16.2 chaperone biomarkers predicts the penetrance of mutations and lifespan after heat shock. But the physiological mechanisms by which cells express different amounts of the biomarker were unknown. Here, we used an in vivo microscopy approach to dissect the mechanisms of cell-to-cell variation in hsp-16.2 biomarker expression, focusing on the intestines, which generate most signal. We found both intrinsic noise and signaling noise are low. The major axis of cell-to-cell variation in gene expression is composed of general differences in protein dosage. Thus, hsp-16.2 biomarkers reveal states of high or low effective dosages for many genes. It is possible that natural variation in protein dosage or chaperone activity may account for missing heritability of some traits.

systems biology↗

bioRxiv2017

High-Resolution Maps of Mouse Reference Populations

Genetic reference panels are widely used to map complex, quantitative traits in model organisms. We have generated new high-resolution genetic maps of 259 mouse inbred strains from recombinant inbred strain panels (C57BL/6J x DBA/2J, ILS/IbgTejJ x ISS/IbgTejJ, C57BL/6J x A/J) and chromosome substitution strain panels (C57BL/6J-Chr# , C57BL/6J-Chr# , C57BL/6JChr# ). We genotyped all samples using the Affymetrix Mouse Diversity Array with an average inter-marker spacing of 4.3kb. The new genetic maps provide increased precision in the localization of recombination breakpoints compared to the previous maps. Although the strains were presumed to be fully inbred, we found residual heterozygosity in 40% of individual mice from five of the six panels. We also identified de novo deletions and duplications, in homozygous or heterozygous state, ranging in size from 21kb to 8.4Mb. Almost two-thirds (46 out of 76) of these deletions overlap exons of protein coding genes and may have phenotypic consequences. Twenty-nine putative gene conversions were identified in the chromosome substitution strains. We find that gene conversions are more likely to occur in regions where the homologous chromosomes are more similar. The raw genotyping data and genetic maps of these strain panels are available at http://churchill-lab.jax.org/website/MDA.

genetics↗