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At least 667 records · Page 37
All sourcesNASA NTRSDOE OSTI
NASA NTRS2016

The Muscles Treasury Survey. I. Motivation and Overview

Ground- and space-based planet searches employing radial velocity techniques and transit photometry have detected thousands of planet-hosting stars in the Milky Way. With so many planets discovered, the next step toward identifying potentially habitable planets is atmospheric characterization. While the Sun-Earth system provides a good framework for understanding the atmospheric chemistry of Earth-like planets around solar-type stars, the observational and theoretical constraints on the atmospheres of rocky planets in the habitable zones (HZs) around low-mass stars (K and M dwarfs) are relatively few. The chemistry of these atmospheres is controlled by the shape and absolute flux of the stellar spectral energy distribution (SED), however, flux distributions of relatively inactive low-mass stars are poorly understood at present. To address this issue, we have executed a panchromatic (X-ray to mid-IR) study of the SEDs of 11 nearby planet-hosting stars, the Measurements of the Ultraviolet Spectral Characteristics of Low-mass Exoplanetary Systems (MUSCLES) Treasury Survey. The MUSCLES program consists visible observations from Hubble and ground-based observatories. Infrared and astrophysically inaccessible wavelengths (EUV and Lyalpha) are reconstructed using stellar model spectra to fill in gaps in the observational data. In this overview and the companion papers describing the MUSCLES survey, we show that energetic radiation (X-ray and ultraviolet) is present from magnetically active stellar atmospheres at all times for stars as late as M6. The emission line luminosities of C IV and Mg II are strongly correlated with band-integrated luminosities and we present empirical relations that can be used to estimate broadband FUV and XUV (is equivalent to X-ray + EUV) fluxes from individual stellar emission line measurements. We find that while the slope of the SED, FUV/NUV, increases by approximately two orders of magnitude form early K to late M dwarfs (approximately equal 0.01-1), the absolute FUV and XUV flux levels at their corresponding HZ distances are constant to within factors of a few, spanning the range 10-70 erg per (sq cm) s in the HZ. Despite the lack of strong stellar activity indicators in their optical spectra, several of the M dwarfs in our sample show spectacular UV flare emission in their light curves. We present an example with flare/quiescent ultraviolet flux ratios of the order of 100:1 where the transition region energy output during the flare is comparable to the total quiescent luminosity of the star E(sub flare)(UV) approximately 0.3 L(sub *) delta (t) (delta t = 1 s). Finally, we interpret enhanced L(line)/L(sub Bol) ratios for C IV and N V as tentative observational evidence for the interaction of planets with large planetary mass-to-orbital distance ratios (M(sub plan)/A(sub plan)) with the transition regions of their host stars.

Infrared and astrophysically inaccessible waveleng↗
NASA NTRSDate not supplied

Development of Lunar EVA Fitness for Duty Standards for Aerobic Capacity and Muscle Strength

Current aerobic Fitness Standards for NASA astronauts are based on peak aerobic capacity (i.e. VO2peak (ml/kg/min))and are related to aerobic metabolic requirements for Extravehicular Activity (EVA) in microgravity and in 1 g operational environments. Standards for muscle strength need to be developed. Fitness for Duty Standards for partial gravity EVA (e.g. 1/6 g EVA on the Lunar surface) are not developed in terms of aerobic fitness and muscle strength. Defining thresholds for aerobic fitness and muscle strength will help to provide guidance in determining recommendations for optimal fitness necessary for partial g EVA success.

D Frisco↗
NASA NTRS2021

The Chain-link Actuator: Exploiting the Bending Stiffness of McKibben Artificial Muscles to Achieve Larger Contraction Ratios

McKibben artificial muscles, comprised of an ex-pandable bladder wrapped in a double-helix-braided sheath,have the ability to generate forces without restricting motion tooccur exclusively along the direction of actuation. This makesthem attractive for a variety of applications including soft,wearable, and biomimetic robots. Despite their advantages, thetheoretical maximum contraction ratio of McKibben muscles isonly 36.3%, which restricts the range of motion of the systemsthey actuate. This work introduces a novel ‘chain-link actuator’that exploits the bending stiffness of McKibben muscles toachieve contraction ratios of more than 50%. A static modelthat captures the relationship between pressure, displacement,and force is presented and validated on several real chain-linkactuator systems.

Daniel Bruder↗
NASA NTRSDate not supplied

Temporal Changes in Astronauts’ Muscle and Cardiorespiratory Physiology Before, During, and After Spaceflight

NASA’s planned space exploration missions will require astronauts to safely perform extravehicular activity (EVA) and to safely egress vehicles in a variety of landing scenarios. Prolonged exposure to spaceflight decreases cardiovascular and sensorimotor function, causes loss of bone mineral density, reduces muscle mass and strength, and ultimately diminishes tolerance for physical activity. Although exercise can help mitigate these spaceflight-induced physiological decrements, little is known regarding the time-course of changes in muscle and aerobic performance during spaceflight. Furthermore, these exercise countermeasures are not fully protective. For example, maximal aerobic capacity (VO2pk), lower body muscle cross-sectional area, and strength all decrease by about 10% to 15% after long-duration missions on the International Space Station (ISS). Future long-duration space missions beyond Low Earth Orbit will employ exploration vehicles with less robust exercise hardware and more constrained exercise capabilities (e.g., less operational volume, less active exercise time) than provided on the ISS. Thus, countermeasures will need to be optimized to protect crew health and performance on exploration-class missions lasting up to 3 years. This requires a more detailed understanding of the dynamic effects of spaceflight on human health and performance, the ability of exercise to protect against this deconditioning, and the interaction of exercise with interrelated factors like nutrition, sleep, and environmental conditions.

N.C. Strock↗
NASA NTRSDate not supplied

Temporal Changes in Astronauts’ Muscle and Cardiorespiratory Physiology Before, During, and After Spaceflight

NASA’s planned space exploration missions will require astronauts to safely perform extravehicular activity (EVA) and to safely egress vehicles in a variety of landing scenarios. Prolonged exposure to spaceflight decreases cardiovascular and sensorimotor function, causes loss of bone mineral density, reduces muscle mass and strength, and ultimately diminishes tolerance for physical activity. Although exercise can help mitigate these spaceflight-induced physiological decrements, little is known regarding the time-course of changes in muscle and aerobic performance during spaceflight. Furthermore, these exercise countermeasures are not fully protective. For example, maximal aerobic capacity (VO2pk), lower body muscle cross-sectional area, and strength all decrease by about 10% to 15% after long-duration missions on the International Space Station (ISS). Future long-duration space missions beyond Low Earth Orbit will employ exploration vehicles with less robust exercise hardware and more constrained exercise capabilities (e.g., less operational volume, less active exercise time) than provided on the ISS. Thus, countermeasures will need to be optimized to protect crew health and performance on exploration-class missions lasting up to 3 years. This requires a more detailed understanding of the dynamic effects of spaceflight on human health and performance, the ability of exercise to protect against this deconditioning, and the interaction of exercise with interrelated factors like nutrition, sleep, and environmental conditions.

N. Strock↗
NASA NTRS2003

Transcriptional regulation of IGF-I expression in skeletal muscle

The present study investigated the role of transcription in the regulation of insulin-like growth factor (IGF)-I expression in skeletal muscle. RT-PCR was used to determine endogenous expression of IGF-I pre-mRNA and mRNA in control (Con) and functionally overloaded (FO) rat plantaris. The transcriptional activities of five different-length IGF-I promoter fragments controlling transcription of a firefly luciferase (FLuc) reporter gene were tested in vitro by transfection of myoblasts or in vivo during FO by direct gene transfer into the plantaris. Increased endogenous IGF-I gene transcription during 7 days of plantaris FO was evidenced by an approximately 140-160% increase (P < 0.0001) in IGF-I pre-mRNA (a transcriptional marker). IGF-I mRNA expression also increased by approximately 90% (P < 0.0001), and it was correlated (R = 0.93; P < 0.0001) with the pre-mRNA increases. The three longest IGF-I exon 1 promoters induced reporter gene expression in proliferating C2C12 and L6E9 myoblasts. In differentiated L6E9 myotubes, promoter activity increased approximately two- to threefold over myoblasts. Overexpression of calcineurin and MyoD increased the activity of the -852/+192 promoter in C2C12 myotubes by approximately 5- and approximately 18-fold, respectively. However, FO did not induce these exogenous promoter fragments. Nevertheless, the present findings are consistent with the hypothesis that the IGF-I gene is transcriptionally regulated during muscle hypertrophy in vivo as evidenced by the induction of the endogenous IGF-I pre-mRNA during plantaris FO. The exon 1 promoter region of the IGF-I gene is sufficient to direct inducible expression in vitro; however, an in vivo response to FO may require elements outside the -852/+346 region of the exon 1 IGF-I promoter or features inherent to the endogenous IGF-I gene.

Non-NASA Center↗
NASA NTRS2003

Protein turnover in atrophying muscle: from nutritional intervention to microarray expression analysis

PURPOSE OF REVIEW: In response to decreased usage, skeletal muscle undergoes adaptive reductive remodeling due to the decrease in tension on the weight bearing components of the musculo-skeletal system. This response occurs with uncomplicated disuse (e.g. bed rest, space flight), as a secondary consequence of several widely prevalent chronic diseases for which activity is reduced (e.g. chronic obstructive pulmonary disease and chronic heart failure) and is part of the aging process. The problem is therefore one of considerable clinical importance. RECENT FINDINGS: The impaired function and exercise intolerance is related more to the associated muscle wasting rather than to the specific organ system primarily impacted by the disease. Progress has continued in describing the use of anabolic drugs and dietary manipulation. The major advance in the field has been: (i) the discovery of the atrogin-1 gene and (ii) the application of microarray expression analysis and proteomics with the objectives of obtaining comprehensive understanding of the pathways changed with disuse atrophy. SUMMARY: Disuse atrophy is a common clinical problem. There is a need for therapeutic interventions that do not involve exercise. A better understanding of the changes, particularly at the molecular level, could indicate hitherto unsuspected sites for nutritional and pharmacological intervention.

Non-NASA Center↗
NASA NTRS1988

Problems in analysis of data from muscles of rats flown in space

Comparison of hindlimb muscles of rats flown on Spacelab-3 or tail-traction-suspended showed that 11-17 h reloading post-flight might have altered the results. Soleus atrophied, plantaris, gastrocnemius and extensor digitorum longus grew slower, and tibialis anterior grew normally. In both flight and simulated soleus and plantaris, higher tyrosine and greater glutamine/glutamate ratio indicated negative protein balance and increased glutamine production, respectively, relative to controls. Aspartate was lower in these muscles. Reloading generally decreased tyrosine, but increased aspartate and glutamine/glutamate. These data showed that at 12 h of reloading after flight is characterized by reversal to varying extents of effects of unloading.

Non-NASA Center↗
NASA NTRS1999

Five myofibrillar lesion types in eccentrically challenged, unloaded rat adductor longus muscle--a test model

Sarcomere disruptions are observed in the adductor longus (AL) muscles following voluntary reloading of spaceflown and hindlimb suspension unloaded (HSU) rat, which resemble lesions in eccentrically challenged muscle. We devised and tested an eccentric contraction (ECCON) test system for the 14-day HSU rat AL. Six to 7 hours following ECCON, ALs were fixed to allow immunostaining and electron microscopy (EM). Toluidine blue-stained histology semithin sections were screened for lesion density (#/mm2). Serial semithin sections from the ECCON group were characterized for myosin immunointensity of lesions. Five myofibrillar lesion types were identified in histological semithin sections: focal contractions; wide A-bands; opaque areas; missing A-bands; and hyperstretched sarcomeres. Lesion density by type was greater for ECCON than NonECCON ALs (P< or =0.05; focal contractions and opaque regions). Lesion density (#-of-all-five-types/mm2) was significantly different (ECCON: 23.91+/-10.58 vs. NonECCON: 5.48+/-1.28, P< or =0.05; ECCON vs. SHAM: 0.00+/-0.00; P< or = 0.025). PostECCON optimal tension decreased (Poi-drop, 17.84+/-4.22%) and was correlated to lesion density (R2=0.596), but prestretch tension demonstrated the highest correlation with lesion density (R2=0.994). In lesions, the darkly staining A-band lost the normally organized thick filament alignment to differing degrees across the different lesion types. Ranking the five lesion types by a measure of lesion length deformation (hypercontracted to hyperstretched) at the light microscopy level, related to the severity of thick filament registry loss across the lesion types at the electron microscopic level. This ranking suggested that the five lesion types seen in semithin sections at the light level represented a lesion progression sequence and paralleled myosin immunostaining loss as the distorted A-band filaments spread across the hyperlengthening lesion types. Lesion ultrastructure indicated damage involved calcium homeostasis loss (focal contraction lesions) and "thick-filament-centering" failure of titin (wide A-band lesions) in the early stages of lesion development.

NASA Discipline Musculoskeletal↗
NASA NTRS1998

Disproportionate loss of thin filaments in human soleus muscle after 17-day bed rest

Previously we reported that, after 17-day bed rest unloading of 8 humans, soleus slow fibers atrophied and exhibited increased velocity of shortening without fast myosin expression. The present ultrastructural study examined fibers from the same muscle biopsies to determine whether decreased myofilament packing density accounted for the observed speeding. Quantitation was by computer-assisted morphometry of electron micrographs. Filament densities were normalized for sarcomere length, because density depends directly on length. Thick filament density was unchanged by bed rest. Thin filaments/microm2 decreased 16-23%. Glycogen filled the I band sites vacated by filaments. The percentage decrease in thin filaments (Y) correlated significantly (P < 0.05) with the percentage increase in velocity (X), (Y = 0.1X + 20%, R2 = 0.62). An interpretation is that fewer filaments increases thick to thin filament spacing and causes earlier cross-bridge detachment and faster cycling. Increased velocity helps maintain power (force x velocity) as atrophy lowers force. Atrophic muscles may be prone to sarcomere reloading damage because force/microm2 was near normal, and force per thin filament increased an estimated 30%.

Non-NASA Center↗
NASA NTRS1997

Near-infrared spectroscopy for monitoring of tissue oxygenation of exercising skeletal muscle in a chronic compartment syndrome model

Variations in the levels of muscle hemoglobin and of myoglobin oxygen saturation can be detected non-invasively with near-infrared spectroscopy. This technique could be applied to the diagnosis of chronic compartment syndrome, in which invasive testing has shown increased intramuscular pressure associated with ischemia and pain during exercise. We simulated chronic compartment syndrome in ten healthy subjects (seven men and three women) by applying external compression, through a wide inflatable cuff, to increase the intramuscular pressure in the anterior compartment of the leg. The tissue oxygenation of the tibialis anterior muscle was measured with near-infrared spectroscopy during gradual inflation of the cuff to a pressure of forty millimeters of mercury (5.33 kilopascals) during fourteen minutes of cyclic isokinetic dorsiflexion and plantar flexion of the ankle. The subjects exercised with and without external compression. The data on tissue oxygenation for each subject then were normalized to a scale of 100 per cent (the baseline value, or the value at rest) to 0 per cent (the physiological minimum, or the level of oxygenation achieved by exercise to exhaustion during arterial occlusion of the lower extremity). With external compression, tissue oxygenation declined at a rate of 1.4 +/- 0.3 per cent per minute (mean and standard error) during exercise. After an initial decrease at the onset, tissue oxygenation did not decline during exercise without compression. The recovery of tissue oxygenation after exercise was twice as slow with compression (2.5 +/- 0.6 minutes) than it was without the use of compression (1.3 +/- 0.2 minutes).

NASA Discipline Musculoskeletal↗
NASA NTRS1995

Adaptive responses of GLUT-4 and citrate synthase in fast-twitch muscle of voluntary running rats

Glucose transporter (GLUT-4) protein, hexokinase, and citrate synthase (proteins involved in oxidative energy production from blood glucose catabolism) increase in response to chronically elevated neuromuscular activity. It is currently unclear whether these proteins increase in a coordinated manner in response to this stimulus. Therefore, voluntary wheel running (WR) was used to chronically overload the fast-twitch rat plantaris muscle and the myocardium, and the early time courses of adaptative responses of GLUT-4 protein and the activities of hexokinase and citrate synthase were characterized and compared. Plantaris hexokinase activity increased 51% after just 1 wk of WR, whereas GLUT-4 and citrate synthase were increased by 51 and 40%, respectively, only after 2 wk of WR. All three variables remained comparably elevated (+50-64%) through 4 wk of WR. Despite the overload of the myocardium with this protocol, no substantial elevations in these variables were observed. These findings are consistent with a coordinated upregulation of GLUT-4 and citrate synthase in the fast-twitch plantaris, but not in the myocardium, in response to this increased neuromuscular activity. Regulation of hexokinase in fast-twitch muscle appears to be uncoupled from regulation of GLUT-4 and citrate synthase, as increases in the former are detectable well before increases in the latter.

Non-NASA Center↗
NASA NTRS1992

Muscle fatigue in frog semitendinosus: role of intracellular pH

The purpose of this study was to utilize glass microelectrodes to characterize the intracellular pH (pHi) before and during recovery from fatigue in the frog semitendinosus (ST) muscle. A second objective was to evaluate the relationship between pHi and contractile function. The frog ST muscle (22 degrees C) was fatigued by direct electrical stimulation with 100-ms 150-Hz trains at 1/s for 5 min. Peak tetanic force (Po) was reduced to 8.5% of initial force and recovered in a biphasic manner, returning to the resting value by 40 min. Resting pHi was 7.00 +/- 0.02 (n = 37) and declined with fatigue to an average value of 6.42 at 3 min of recovery. During recovery pHi significantly increased and by 25 min had returned to the prefatigue value. The pHi recovery was highly correlated to the slow phase of Po recovery (r = 0.98, P less than 0.001). The mean resting membrane potential was -78 +/- 1.0 mV (n = 42) and at 3 min of recovery was depolarized to -67 +/- 4 mV. Both the peak rate of twitch force development (+dP/dt) (r = 0.99, P less than 0.001) and decline (-dP/dt) (r = 0.94, P less than 0.014) were highly correlated to pHi during the slow phase of recovery. Contraction time (CT) and one-half relaxation time (1/2RT) increased significantly and recovered exponentially. The recovery of CT and 1/2RT were both significantly correlated to pHi (r = -0.93, P less than 0.001 and r = -0.86, P less than 0.001 for CT and 1/2RT, respectively).(ABSTRACT TRUNCATED AT 250 WORDS).

NASA Discipline Musculoskeletal↗
DOE OSTI2019

A MUSCL-SCNI approach for meshfree modeling of shock waves in fluids

Here, a stable and nodally integrated meshfree formulation for modeling shock waves in fluids is developed. The reproducing kernel approximation is employed to discretize the conservation equations for compressible flow, and a flux vector splitting approach is applied to allow proper numerical treatments for the advection and pressure parts, respectively, based on the characteristics of each flux term. To capture the essential shock physics in fluids, including the Rankine–Hugoniot jump conditions and the entropy condition, local Riemann enrichment is introduced under the stabilized conforming nodal integration (SCNI) framework. Meanwhile, numerical instabilities associated with the advection flux are eliminated by adopting a modified upwind scheme. To further enhance accuracy, a MUSCL-type method is introduced in conjunction with an oscillation limiter to avoid Gibbs phenomenon and ensure monotonic piecewise linear reconstruction in the smooth region. The present meshfree formulation is free from tunable artificial parameters and is capable of capturing shock and rarefaction waves without over/undershoots. Finally, several numerical examples are analyzed to demonstrate the effectiveness of the proposed MUSCL-SCNI approach in meshfree modeling of complex shock phenomena, including shock diffraction, shock–vortex interaction, and high energy explosion processes.

42 ENGINEERING↗
DOE OSTI2012

Determination of osteogenic or adipogenic lineages in muscle-derived stem cells (MDSCs) by a collagen-binding peptide (CBP) derived from bone sialoprotein (BSP)

Highlights: Black-Right-Pointing-Pointer CBP sequence is identified from BSP and has collagen binding activity. Black-Right-Pointing-Pointer CBP directly activates the MAPK signaling, especially ERK1/2. Black-Right-Pointing-Pointer CBP increase osteoblastic differentiation by the activation of Runx2. Black-Right-Pointing-Pointer CBP decrease adipogenic differentiation by the inhibition of PPAR{gamma}. -- Abstract: Bone sialoprotein (BSP) is a mineralized, tissue-specific, non-collagenous protein that is normally expressed only in mineralized tissues such as bone, dentin, cementum, and calcified cartilage, and at sites of new mineral formation. The binding of BSP to collagen is thought to be important for initiating bone mineralization and bone cell adhesion to the mineralized matrix. Several recent studies have isolated stem cells from muscle tissue, but their functional properties are still unclear. In this study, we examined the effects of a synthetic collagen-binding peptide (CBP) on the differentiation efficiency of muscle-derived stem cells (MDSCs). The CBP sequence (NGVFKYRPRYYLYKHAYFYPHLKRFPVQ) corresponds to residues 35-62 of bone sialoprotein (BSP), which are located within the collagen-binding domain in BSP. Interestingly, this synthetic CBP inhibited adipogenic differentiation but increased osteogenic differentiation in MDSCs. The CBP also induced expression of osteoblastic marker proteins, including alkaline phosphatase (ALP), type I collagen, Runt-related transcription factor 2 (Runx2), and osteocalcin; prevented adipogenic differentiation in MDSCs; and down-regulated adipose-specific mRNAs, such as adipocyte protein 2 (aP2) and peroxisome proliferator-activated receptor {gamma}. The CBP increased Extracellular signal-regulated kinases (ERK) 1/2 protein phosphorylation, which is important in lineage determination. These observations suggest that this CBP determines the osteogenic or adipogenic lineage in MDSCs by activating ERK1/2. Taken together, a novel CBP could be a useful candidate for regenerating bone and treating osteoporosis, which result from an imbalance in osteogenesis and adipogenesis differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Divergent effects of 17-{beta}-estradiol on human vascular smooth muscle and endothelial cell function diminishes TNF-{alpha}-induced neointima formation

Highlights: Black-Right-Pointing-Pointer TNF-{alpha} augments neointimal hyperplasia in human saphenous vein. Black-Right-Pointing-Pointer TNF-{alpha} induces detrimental effects on endothelial and smooth muscle cell function. Black-Right-Pointing-Pointer Estradiol exerts modulatory effects on TNF-induced vascular cell functions. Black-Right-Pointing-Pointer The modulatory effects of estradiol are discriminatory and cell-type specific. -- Abstract: Coronary heart disease (CHD) is a condition characterized by increased levels of proinflammatory cytokines, including tumor necrosis factor-{alpha} (TNF-{alpha}). TNF-{alpha} can induce vascular endothelial cell (EC) and smooth muscle cell (SMC) dysfunction, central events in development of neointimal lesions. The reduced incidence of CHD in young women is believed to be due to the protective effects of estradiol (E2). We therefore investigated the effects of TNF-{alpha} on human neointima formation and SMC/EC functions and any modulatory effects of E2. Saphenous vein (SV) segments were cultured in the presence of TNF-{alpha} (10 ng/ml), E2 (2.5 nM) or both in combination. Neointimal thickening was augmented by incubation with TNF-{alpha}, an effect that was abolished by co-culture with E2. TNF-{alpha} increased SV-SMC proliferation in a concentration-dependent manner that was optimal at 10 ng/ml (1.5-fold increase), and abolished by E2 at all concentrations studied (1-50 nM). Surprisingly, E2 itself at low concentrations (1 and 5 nM) stimulated SV-SMC proliferation to a level comparable to that of TNF-{alpha} alone. SV-EC migration was significantly impaired by TNF-{alpha} (42% of control), and co-culture with E2 partially restored the ability of SV-EC to migrate and repair the wound. In contrast, TNF-{alpha} increased SV-SMC migration by 1.7-fold, an effect that was completely reversed by co-incubation with E2. Finally, TNF-{alpha} potently induced ICAM-1 and VCAM-1 expression in both SV-EC and SV-SMC. However there was no modulation by E2 in either cell-type. In conclusion, TNF-{alpha} induced SV neointima formation, increased SMC proliferation and migration, impaired SV-EC migration and increased expression of adhesion molecules. E2 exerted distinct cell-type and function-specific modulation, the mechanisms underlying which are worthy of further detailed study.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Leptin promotes osteoblast differentiation and mineralization of primary cultures of vascular smooth muscle cells by inhibiting glycogen synthase kinase (GSK)-3{beta}

Highlights: Black-Right-Pointing-Pointer Leptin promotes osteoblast differentiation of primary smooth muscle cells. Black-Right-Pointing-Pointer Leptin regulates the expression of genes involved in osteoblast differentiation. Black-Right-Pointing-Pointer Constitutively active GSK-3{beta} attenuates leptin-induced osteoblast differentiation. Black-Right-Pointing-Pointer This suggests that leptin signals through GSK-3{beta} to promote osteoblast differentiation. -- Abstract: In this study, we begin to investigate the underlying mechanism of leptin-induced vascular calcification. We found that treatment of cultured bovine aortic smooth muscle cells (BASMCs) with leptin (0.5-4 {mu}g/ml) induced osteoblast differentiation in a dose-dependent manner. Furthermore, we found that leptin significantly increased the mRNA expression of osteopontin and bone sialoprotein, while down-regulating matrix gla protein (MGP) expression in BASMCs. Key factors implicated in osteoblast differentiation, including members of the Wnt signaling pathway, were examined. Exposure to leptin enhanced phosphorylation of GSK-3{beta} on serine-9 thereby inhibiting activity and promoting the nuclear accumulation of {beta}-catenin. Transfection of BASMCs with an adenovirus that expressed constitutively active GSK-3{beta} (Ad-GSK-3{beta} S9A) resulted in a >2-fold increase in GSK-3{beta} activity and a significant decrease in leptin-induced alkaline phosphatase (ALP) activity. In addition, qRT-PCR analysis showed that GSK-3{beta} activation resulted in a significant decrease in the expression of osteopontin and bone sialoprotein, but a marked increase in MGP mRNA expression. When taken together, our results suggest a mechanism by which leptin promotes osteoblast differentiation and vascular calcification in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Piperlongumine inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling

Highlights: Black-Right-Pointing-Pointer Anti-atherogenic effect of PL was examined using partial carotid ligation model in ApoE KO mice. Black-Right-Pointing-Pointer PL prevented atherosclerotic plaque development, VSMCs proliferation, and NF-{kappa}B activation. Black-Right-Pointing-Pointer Piperlongumine reduced vascular smooth muscle cell activation through PDGF-R{beta} and NF-{kappa}B-signaling. Black-Right-Pointing-Pointer PL may serve as a new therapeutic molecule for atherosclerosis treatment. -- Abstract: Piperlongumine (piplartine, PL) is an alkaloid found in the long pepper (Piper longum L.) and has well-documented anti-platelet aggregation, anti-inflammatory, and anti-cancer properties; however, the role of PL in prevention of atherosclerosis is unknown. We evaluated the anti-atherosclerotic potential of PL in an in vivo murine model of accelerated atherosclerosis and defined its mechanism of action in aortic vascular smooth muscle cells (VSMCs) in vitro. Local treatment with PL significantly reduced atherosclerotic plaque formation as well as proliferation and nuclear factor-kappa B (NF-{kappa}B) activation in an in vivo setting. PL treatment in VSMCs in vitro showed inhibition of migration and platelet-derived growth factor BB (PDGF-BB)-induced proliferation to the in vivo findings. We further identified that PL inhibited PDGF-BB-induced PDGF receptor beta activation and suppressed downstream signaling molecules such as phospholipase C{gamma}1, extracellular signal-regulated kinases 1 and 2 and Akt. Lastly, PL significantly attenuated activation of NF-{kappa}B-a downstream transcriptional regulator in PDGF receptor signaling, in response to PDGF-BB stimulation. In conclusion, our findings demonstrate a novel, therapeutic mechanism by which PL suppresses atherosclerosis plaque formation in vivo.

60 APPLIED LIFE SCIENCES↗