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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Structural OFF/ON transitions of myosin in relaxed porcine myocardium predict calcium-activated force

Contraction in striated muscle is initiated by calcium binding to troponin complexes, but it is now understood that dynamic transition of myosin between resting, ordered OFF states on thick filaments and active, disordered ON states that can bind to thin filaments is critical in regulating muscle contractility. These structural OFF to ON transitions of myosin are widely assumed to correspond to transitions from the biochemically defined, energy-sparing, super-relaxed (SRX) state to the higher ATPase disordered-relaxed (DRX) state. Here, in this study, we examined the effect of 2’-deoxy-ATP (dATP), a naturally occurring energy substrate for myosin, on the structural OFF to ON transitions of myosin motors in porcine cardiac muscle thick filaments. Small-angle X-ray diffraction revealed that titrating dATP in relaxation solutions progressively moves the myosin heads from ordered OFF states on the thick filament backbone to disordered ON states closer to thin filaments. Importantly, we found that the structural OFF to ON transitions are not equivalent to the biochemically defined SRX to DRX transitions and that the dATP-induced structural OFF to ON transitions of myosin motors in relaxed muscle are strongly correlated with submaximal force augmentation by dATP. These results indicate that structural OFF to ON transitions of myosin in relaxed muscle can predict the level of force attained in calcium-activated cardiac muscle. Computational modeling and stiffness measurements suggest a final step in the OFF to ON transition may involve a subset of DRX myosins that form weakly bound cross-bridges prior to becoming active force-producing cross-bridges.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Phosphoproteomics Modifications in Women with Rheumatoid Arthritis─Application of Web-Based Software to Enhance Data Visualization

Individuals with rheumatoid arthritis (RA) are at increased risk of functional disability, cardiovascular disease, and obesity, all of which are influenced by dysregulated skeletal muscle. Here, this pilot study aims to identify phosphoproteomics changes in RA skeletal muscle and visualize modifications through development of a web-based app designed to promote user-friendly data interpretation and visualization. NanoLC–MS/MS analysis was performed on vastus lateralis biopsies from three women with RA and matched healthy controls. Differential analysis was performed using the Limma R package. Kinase substrate enrichment analysis (KSEA) predicted changes in kinase activity. RA muscle displayed 35 upregulated and 60 downregulated phosphosites, including the cytoskeletal proteins TTN (Ser33201, Ser33013, Ser20925), NEB (Ser2219, Thr254, Ser33013, Ser20925), FLNA (Ser1459), and LASP1 (Ser146). Compared to healthy controls, KSEA predicted decreased activity of several kinases in RA muscle, including PRKACA and CDKs. All such changes were visualized by use of our web-based app. Overall, phosphoproteome analysis reveals signaling alterations in RA skeletal muscle linked to cytoskeletal proteins, representing candidate disease biomarkers; these modifications can be explored through use of our web-based software.

phosphoproteomics↗
DOE OSTI2020

Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism

Nebulin is a giant protein that winds around the actin filaments in the skeletal muscle sarcomere. Compound-heterozygous mutations in the nebulin gene (NEB) cause typical nemaline myopathy (NM), a muscle disorder characterized by muscle weakness with limited treatment options. We created a mouse model with a missense mutation p.Ser6366Ile and a deletion of NEB exon 55, the Compound-Het model that resembles typical NM. We show that Compound-Het mice are growth-retarded and have muscle weakness. Muscles have a reduced myofibrillar fractional-area and sarcomeres are disorganized, contain rod bodies, and have longer thin filaments. In contrast to nebulin-based severe NM where haplo-insufficiency is the disease driver, Compound-Het mice express normal amounts of nebulin. X-ray diffraction revealed that the actin filament is twisted with a larger radius, that tropomyosin and troponin behavior is altered, and that the myofilament spacing is increased. The unique disease mechanism of nebulin-based typical NM reveals novel therapeutic targets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT)

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Sixty days of head-down tilt bed rest with or without artificial gravity do not affect the neuromuscular secretome

Highlights: • Long-term bed rest with/without artificial gravity does not affect the neuromuscular secretome. • Serum concentrations of markers of muscle wasting are not affected by bed rest/artificial gravity. • C-terminal Agrin Fragment serum concentrations are not affected by bed rest/artificial gravity. • Human centrifugation during bed rest does not have a negative impact on the neuromuscular secretome. Artificial gravity is a potential countermeasure to attenuate effects of weightlessness during long-term spaceflight, including losses of muscle mass and function, possibly to some extent attributable to disturbed neuromuscular interaction. The 60-day AGBRESA bed-rest study was conducted with 24 participants (16 men, 8 women; 33 ± 9 years; 175 ± 9 cm; 74 ± 10 kg; 8 control group, 8 continuous (cAG) and 8 intermittent (iAG) centrifugation) to assess the impact of bed rest with or without daily 30-min continuous/intermittent centrifugation with 1G at the centre of mass. Fasting blood samples were collected before and on day 6, 20, 40 and 57 during 6° head-down tilt bed rest. Concentrations of circulating markers of muscle wasting (GDF-8/myostatin; slow skeletal muscle troponin T; prostaglandin E2), neurotrophic factors (BDNF; GDNF) and C-terminal Agrin Fragment (CAF) were determined by ELISAs. Creatine kinase activity was assessed by colorimetric enzyme assay. Repeated-measures ANOVAs were conducted with TIME as within-subject, and INTERVENTION and SEX as between-subject factors. The analyses revealed no significant effect of bed rest or sex on any of the parameters. Continuous or intermittent artificial gravity is a safe intervention that does not have a negative impact of the neuromuscular secretome.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Myosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads

Muscle contraction is produced via the interaction of myofilaments and is regulated so that muscle performance matches demand. Myosin-binding protein C (MyBP-C) is a long and flexible protein that is tightly bound to the thick filament at its C-terminal end (MyBP-C C8C10 ), but may be loosely bound at its middle- and N-terminal end (MyBP-C C1C7 ) to myosin heads and/or the thin filament. MyBP-C is thought to control muscle contraction via the regulation of myosin motors, as mutations lead to debilitating disease. We use a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-C C1C7 domains of fast MyBP-C in permeabilized skeletal muscle. We show that cleavage leads to alterations in crossbridge kinetics and passive structural signatures of myofilaments that are indicative of a shift of myosin heads towards the ON state, highlighting the importance of MyBP-C C1C7 to myofilament force production and regulation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Bioaccumulation of Mercury and Radiocesium in Waterfowl Introduced to a Site with Legacy Contamination

Despite the propensity of waterfowl species to readily accumulate anthropogenic contaminants within polluted environments, few studies have examined bioaccumulation rates over time when entering such a contaminated site. We examined mercury (Hg) and radiocesium ( 137 Cs) bioaccumulation over time in two waterfowl species released into a wetland system containing legacy contamination on the US Department of Energy's Savannah River Site in South Carolina. Released birds were collected at select time intervals over an exposure period of 94 days. We quantified total Hg concentrations in blood, muscle, and liver tissues, and 137 Cs activity in whole-body and muscle tissues. The relationship between the contaminant burdens of different body tissue types was examined over time. Likely a result of microhabitat selection, mallards in our study readily accumulated both Hg and 137 Cs at consistent rates over time within our study system, while ring-neck ducks did not. The findings demonstrated that whole blood can be used as a robust, nondestructive sampling alternative to estimate Hg burdens within muscle and liver, and whole-body 137 Cs activity is a good predictor of muscle burdens. Understanding such bioaccumulation information in waterfowl is useful for the assessment of the potential health risk in wildlife, as well as being important for human risk assessment toward the consumption of popular game species. Environ Toxicol Chem 2022;41:2479–2487. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

The structural and functional integrities of porcine myocardium are mostly preserved by cryopreservation

Structural and functional studies of heart muscle are important to gain insights into the physiological bases of cardiac muscle contraction and the pathological bases of heart disease. While fresh muscle tissue works best for these kinds of studies, this is not always practical to obtain, especially for heart tissue from large animal models and humans. Conversely, tissue banks of frozen human hearts are available and could be a tremendous resource for translational research. It is not well understood, however, how liquid nitrogen freezing and cryostorage may impact the structural integrity of myocardium from large mammals. In this study, we directly compared the structural and functional integrity of never-frozen to previously frozen porcine myocardium to investigate the consequences of freezing and cryostorage. X-ray diffraction measurements from hydrated tissue under near-physiological conditions and electron microscope images from chemically fixed porcine myocardium showed that prior freezing has only minor effects on structural integrity of the muscle. Furthermore, mechanical studies similarly showed no significant differences in contractile capabilities of porcine myocardium with and without freezing and cryostorage. These results demonstrate that liquid nitrogen preservation is a practical approach for structural and functional studies of myocardium.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches

A review of recent animal models of amyotrophic lateral sclerosis showed a large number of miRNAs had altered levels of expression in the brain and spinal cord, motor neurons of spinal cord and brainstem, and hypoglossal, facial, and red motor nuclei and were mostly upregulated. Among the miRNAs found to be upregulated in two of the studies were miR-21, miR-155, miR-125b, miR-146a, miR-124, miR-9, and miR-19b, while those downregulated in two of the studies included miR-146a, miR-29, miR-9, and miR-125b. A change of direction in miRNA expression occurred in some tissues when compared (e.g., miR-29b-3p in cerebellum and spinal cord of wobbler mice at 40 days), or at different disease stages (e.g., miR-200a in spinal cord of SOD1(G93A) mice at 95 days vs. 108 and 112 days). In the animal models, suppression of miR-129-5p resulted in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and tended to improve motor neuron survival in the SOD1(G93A) mouse model. Suppression of miR-155 was also associated with increased lifespan, while lowering of miR-29a tended to improve lifespan in males and increase muscle strength in SOD1(G93A) mice. Overexpression of members of miR-17~92 cluster improved motor neuron survival in SOD1(G93A) mice. Treatment with an artificial miRNA designed to target hSOD1 increased lifespan and improved muscle strength in SOD1(G93A) animals. Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific miRNAs whose suppression or directed against hSOD1 results in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and improved motor neuron survival in SOD1(G93A) animals.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Systems and methods for approximating musculoskeletal dynamics

An approximation method and system are provided for more quickly controlling a prosthetic or other device by reducing computational processing time in a muscle model that can be used to control the prosthetic. For a given muscle, the approximation method can quickly compute polynomial structures for a muscle length and for each associated moment arms, which may be used to generate a torque for a joint position of a physics model. The physics model, in turn, produces a next joint position and velocity data for driving a prosthetic. The approximation method expands the polynomial structures as long as expansion is possible and sufficiently beneficial. The computations can be performed quickly by expanding the polynomial structures in a way that constrains the muscle length polynomial to the moment arm polynomial structures, and vice versa.

Sobinov, Anton↗
DOE OSTI2025

Per- and polyfluoroalkyl substances (PFAS) in fish collected from the Rio Grande and reservoirs in northern New Mexico

Per- and polyfluoroalkyl substances (PFAS) are a group of industrial and commercial chemicals widely used throughout the world due to their beneficial chemical properties. Because of their widespread use, their chemical stability, and their ability to be transported over long distances through atmospheric deposition and movement through waterways, PFAS are found throughout most aquatic ecosystems; yet large sampling gaps exist among reservoir and river ecosystems in the desert southwest of the United States. In this study, we examine PFAS concentrations in the tissue of fish (catfish [channel and blue], common carp, smallmouth bass, northern pike, walleye, white crappie and white sucker) collected in northern New Mexico, including examining PFAS composition and concentration relative to trophic level distribution. We collected fish from two man-made reservoirs and from the Rio Grande. We then collected muscle and liver tissues from fish specimens, which were screened for 39 PFAS compounds. We detected PFAS compounds in most fish tissue sampled, including the biomagnification of PFAS compounds within liver samples, with PFOS concentrations ranged from 1.13 to 350.1 (64.4 average) times higher in the liver samples compared to muscle samples. Most PFAS concentrations within muscle samples were within the range of atmospheric transportation previously reported and average tissue concentrations of PFAS were calculated to be 2.02 ± 1.81 ng g -1 . Using stable isotopes as a predictor of trophic-foraging exposure and PFAS concentrations, we noted a correlation between enriched δ 15 N values, which had higher perfluorodecanoic acid concentrations.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2023

Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2

The ACTN2 gene encodes α-actinin 2, located in the Z-disc of the sarcomeres in striated muscle. In this study, we sought to investigate the effects of an ACTN2 missense variant of unknown significance (p.A868T) on cardiac muscle structure and function. Left ventricular free wall samples were obtained at the time of cardiac transplantation from a heart failure patient with the ACTN2 A868T heterozygous variant. This variant is in the EF 3–4 domain known to interact with titin and α-actinin. At the ultrastructural level, ACTN2 A868T cardiac samples presented small structural changes in cardiomyocytes when compared to healthy donor samples. However, contractile mechanics of permeabilized ACTN2 A868T variant cardiac tissue displayed higher myofilament Ca 2+ sensitivity of isometric force, reduced sinusoidal stiffness, and faster rates of tension redevelopment at all Ca 2+ levels. Small-angle X-ray diffraction indicated increased separation between thick and thin filaments, possibly contributing to changes in muscle kinetics. Molecular dynamics simulations indicated that while the mutation does not significantly impact the structure of α-actinin on its own, it likely alters the conformation associated with titin binding. Our results can be explained by two Z-disc mediated communication pathways: one pathway that involves α-actinin’s interaction with actin, affecting thin filament regulation, and the other pathway that involves α-actinin’s interaction with titin, affecting thick filament activation. This work establishes the role of α-actinin 2 in modulating cross-bridge kinetics and force development in the human myocardium as well as how it can be involved in the development of cardiac disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Patterns of Trace Element Accumulation in Waterfowl Restricted to Impoundments Holding Coal Combustion Waste

Waterfowl are often exposed to and readily accumulate anthropogenic contaminants when foraging in polluted environments. Settling impoundments containing coal combustion waste (CCW) enriched in trace elements such as arsenic (As), selenium (Se), and mercury (Hg) are often used by free-ranging migratory and resident waterfowl and represent potential sources for contaminant uptake. To assess accumulation of CCW contaminants, we experimentally restricted waterfowl to a CCW-contaminated impoundment and quantified trace element burdens in blood, muscle, and liver tissues over known periods of exposure (between 3 and 92 d). From these data we developed models 1) to predict elemental bioaccumulation with increased exposure time, and 2) to predict muscle/liver burdens based on concentrations in blood as a nondestructive sampling method. Although Hg and As did not bioaccumulate in our waterfowl, we observed an increase in Se concentrations in muscle, liver, and blood tissues over the duration of our experiment. Furthermore, we found that blood may be used as an effective nondestructive sampling alternative to predict muscle and liver tissue concentrations in birds contaminated with Se and As through dietary exposure. These data provide unique insights into accumulation rates of contaminants for waterfowl utilizing habitats contaminated with CCW and demonstrate the efficacy of nonlethal sampling of waterfowl to quantify contaminant exposure. Environ Toxicol Chem 2020;39:1052–1059.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

The sodium channel Na X : Possible player in excitation–contraction coupling

Abstract The sodium channel Na X (encoded by the SCN7A gene) was originally identified in the heart and skeletal muscle and is structurally similar to the other voltage‐gated sodium channels but does not appear to be voltage gated. Although Na X is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of Na X in these tissues. Transcriptional profiling of ion channels in the heart in a subset of patients with Brugada syndrome revealed an inverse relationship between the expression of Na X and Na V 1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that Na X plays a role in excitation–contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, Na X is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M‐line. Knocking down Na X expression decreased Na V 1.5 mRNA and protein and reduced the inward sodium current ( I Na+ ) following cell depolarization. When the expression of Na V 1.5 was knocked down, ~85% of the I Na+ was reduced consistent with the observations that Na V 1.5 is the main voltage‐gated sodium channel in cardiac muscle and that Na X likely does not directly participate in mediating the I Na+ following depolarization. Silencing Na V 1.5 expression led to significant upregulation of Na X mRNA. Similar to Na V 1.5, Na X protein levels were rapidly downregulated when the intracellular [Ca 2+ ] was increased either by CaCl 2 or caffeine. These data suggest that a relationship exists between Na X and Na V 1.5 and that Na X may play a role in excitation–contraction coupling.

Bogdanovic, Elena↗
DOE OSTI2023

Micromovements and discomfort associated with flight mission with helmet operation tasks with different levels of cognitive workload

When performing stationary tasks under elevated cognitive workload, individuals must perform continual muscle contractions to maintain stability of the body, resulting in fatigue of the postural muscles. When the muscles perform these contractions in a prolonged manner, the body potentially responds through small changes in body movements—micromovements that may lead to discomfort. The study purpose was to evaluate impact of cognitive load on micromovements. The micromovements were measured during three different cognitive workloads; low, medium, and high. The NASA-TLX score was used to evaluate the perceived mental workload and discomfort was assessed by visual analog scale. In total, 60 subjects (30 males and 30 females) were recruited and performed cognitive tasks that simulated flight operations such as changing the radio frequency based on air traffic control messages, balancing the fuel levels in simulated fuel tanks, and aiming a reticle in a designated moving target using the cyclic control. Cognitive load was defined by the frequency of events. Micromovements were defined by changes in the center of pressure (COP) of the seat pan and COP standard deviation. It was found that the high cognitive workloads had the highest NASA-TLX scores including mental demands, temporal demands, and effort. The neck area had the highest overall levels of discomfort followed by upper back. The highest standard deviation for COP shift and number of micromovements occurred for medium cognitive workloads. In conclusion, while there were some interesting trends, few trends reached a statistical significance due to high variability among subjects for the outcome variables.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function

Missense variant Ile79Asn in human cardiac troponin T (cTnT-I79N) has been associated with hypertrophic cardiomyopathy and sudden cardiac arrest in juveniles. cTnT-I79N is located in the cTnT N-terminal (TnT1) loop region and is known for its pathological and prognostic relevance. A recent structural study revealed that I79 is part of a hydrophobic interface between the TnT1 loop and actin, which stabilizes the relaxed (OFF) state of the cardiac thin filament. Given the importance of understanding the role of TnT1 loop region in Ca 2+ regulation of the cardiac thin filament along with the underlying mechanisms of cTnT-I79N-linked pathogenesis, we investigated the effects of cTnT-I79N on cardiac myofilament function. Transgenic I79N (Tg-I79N) muscle bundles displayed increased myofilament Ca 2+ sensitivity, smaller myofilament lattice spacing, and slower crossbridge kinetics. These findings can be attributed to destabilization of the cardiac thin filament’s relaxed state resulting in an increased number of crossbridges during Ca 2+ activation. Additionally, in the low Ca 2+ -relaxed state (pCa8), we showed that more myosin heads are in the disordered-relaxed state (DRX) that are more likely to interact with actin in cTnT-I79N muscle bundles. Dysregulation of the myosin super-relaxed state (SRX) and the SRX/DRX equilibrium in cTnT-I79N muscle bundles likely result in increased mobility of myosin heads at pCa8, enhanced actomyosin interactions as evidenced by increased active force at low Ca 2+ , and increased sinusoidal stiffness. These findings point to a mechanism whereby cTnT-I79N weakens the interaction of the TnT1 loop with the actin filament, which in turn destabilizes the relaxed state of the cardiac thin filament.

59 BASIC BIOLOGICAL SCIENCES↗