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At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
NASA NTRS1991

High-Moisture Diet for Laboratory Rats: Nutrient Analysis, Growth, and Organ Weights

A diet (KSC-25) to be sterilized by irradiation was formulated to contain 66% moisture and to provide the required nutrients for growing rats. Analyses of the irradiated dry diet provided data to evaluate its nutrient content. The diet was evaluated for its ability to supply all nutrients, including water, required by immature rats. Sixteen Sprague-Dawley rats were fed the high-moisture diet with or without access to a water bottle. Rats (n = 16) fed an irradiated purified diet in a meal form with access to a water bottle were the control animals. Feed efficiency, food and water consumption, and growth rate data were collected during the 28-day study. Organ weights were collected on day 28. The test diet met or exceeded the National Research Council (NRC) estimated nutritional requirements for immature laboratory rats. The 66% moisture KSC-25 diet provided all nutrients, including water, required by weanling male Sprague-Dawley rats for growth equivalent to the established purified diet.

Battles, August H.↗
NASA NTRS1999

The Effects of Partial Mechanical Loading and Ibandronate on Skeletal Tissues in the Adult Rat Hindquarter Suspension Model for Microgravity

We report initial data from a suspended rat model that quantitatively relates chronic partial weightbearing to bone loss. Chronic partial weightbearing is our simulation of the effect of limited artificial gravity aboard spacecraft or reduced planetary gravity. Preliminary analysis of bone by PQCT, histomorphometry, mechanical testing and biochemistry suggest that chronic exposure to half of Earth gravity is insufficient to prevent severe bone loss. The effect of episodic full weightbearing activity (Earth Gravity) on rats otherwise at 50% weightbearing was also explored. This has similarity to treatment by an Earth G-rated centrifuge on a spacecraft that normally maintained artificial gravity at half of Earth G. Our preliminary evidence, using the above techniques to analyze bone, indicate that 2 hours daily of full weightbearing was insufficient to prevent the bone loss observed in 50% weightbearing animals. The effectiveness of partial weightbearing and episodic full weightbearing as potential countermeasures to bone loss in spaceflight was compared with treatment by ibandronate. Ibandronate, a long-acting potent bisphosphonate proved more effective in preventing bone loss and associated functionality based upon structure than our first efforts at mechanical countermeasures. The effectiveness of ibandronate was notable by each of the testing methods we used to study bone from gross structure and strength to tissue and biochemistry. These results appear to be independent of generalized systemic stress imposed by the suspension paradigm. Preliminary evidence does not suggest that blood levels of vitamin D were affected by our countermeasures. Despite the modest theraputic benefit of mechanical countermeasures of partial weightbearing and episodic full weightbearing, we know that some appropriate mechanical signal maintains bone mass in Earth gravity. Moreover, the only mechanism that correctly assigns bone mass and strength to oppose regionally specific force applied to bone is mechanical, a process based upon bone strain. Substantial evidence indicates that the specifics of dynamic loading i.e. time-varying forces are critical. Bone strain history is a predictor of the effect that mechanical conditions have on bone structure mass and strength. Using servo-controlled force plates on suspended rats with implanted strain gauges we manipulated impact forces of ambulation in the frequency (Fourier) domain. Our results indicate that high frequency components of impact forces are particularly potent in producing bone strain independent of the magnitude of the peak force or peak energy applied to the leg. Because a servo-system responds to forces produced by the rat's own muscle activity during ambulation, the direction of ground-reaction loads act on bone through the rat's own musculature. This is in distinction to passive vibration of the floor where forces reach bone through the natural filters of soft tissue and joints. Passive vibration may also be effective, but it may or may not increase bone in the appropriate architectural pattern to oppose the forces of normal ambulatory activity. Effectiveness of high frequency mechanical stimulation in producing regional (muscle directed) bone response will be limited by 1. the sensitivity of bone to a particular range of frequencies and 2. the inertia of the muscles, limiting their response to external forces by increasing tension along insertions. We have begun mathematical modeling of normal ambulatory activity. Effectiveness of high frequency mechanical stimulation in producing regional (muscle directed) bone response will be limited by 1. the sensitivity of bone to a particular range of frequencies and 2. the inertia of the muscles, limiting their response to external forces by increasing tension along insertions. We have begun mathematical modeling of the rat forelimb as a transfer function between impact force and bone strain to predict optimal dynamic loading conditions for this system. We plan additional studies of mechanical counter-measures that incorporate improved dynamic loading, features relevant to anticipated evaluation of artificial gravity, exercise regimens and exposure to Martian gravity, The combination of mechanical countermeasures with ibandronate will also be investigated for signs of synergy.

Schultheis, Lester W.↗
NASA NTRS2001

Renal Function of Rats in Response to 37 Days of Head-Down Tilt

Spaceflight induces changes in human renal function, suggesting similar changes may occur in rats. Since rats continue to be the prime mammalian model for study in space, the effects of chronic microgravity on rat renal function should be clarified. Acute studies in rats using the ground-based microgravity simulation model, head-down tilt (HDT), have shown increases in glomerular filtration rate (GFR), electrolyte excretion, and a diuresis. However, long term effects of HDT have not been studied extensively. This study was performed to elucidate rat renal function following long-term simulated microgravity. Chronic exposure to HDT will cause an increase in GFR and electrolyte excretion in rats, similar to acute exposures, and lead to a decrease in the fractional excretion of filtered electrolytes. Experimental animals (HDT, n=10) were tail-suspended for 37 days and renal function compared to ambulatory controls (AMB, n=10). On day 37 of HDT, GFR, osmolal clearance, and electrolyte excretion were decreased, while plasma osmolality and free water clearance were increased. Urine output remained similar between groups. The fractional excretion of the filtered electrolytes was unchanged except for a decrease in the percentage of filtered calcium excreted. Chronic exposure to HDT results in decreased GFR and electrolyte excretion, but the fractional excretion of filtered electrolytes remained primarily unaffected.

Wang, Tommy J.↗
NASA NTRS1997

Calcium Balance in A Rat Space Flight Model

One of the main characteristics of calcium (Ca) metabolism during space flight and the human bed rest model for microgravity is negative Ca balance, attributed, to an increase in urinary Ca excretion and depressed intestinal Ca absorption. No differences or less positive Ca balances are reported after skeletal unloading in similar studies in weaning or juvenile rats. To determine Ca balances and evaluate the Ca endocrine system in mature rats exposed to a space flight model which unloaded the hind limbs by tail suspension, we modified the cage to quantify dietary, fecal and urinary Ca. Five 2-5 d balance periods in 8 loaded (C) and 8 unloaded (S) rats were compared during a 4 week study in 6 month old 490 g male rats. The first period revealed negative balances of -16+/-3 and -14+/-5 mg/d which reflected adaptation to the cages, the change in diet from Purina to AIN 76 and weight loss in both C and S. Average Ca balances in rats fed 0.1% Ca and 0.3% phosphorus (Pi) diets, remained negative in S and were less than C after 6 -10 d (-2.9 vs 0.12 mg/d, p<.05) but not thereafter. In spite of eating 10% more food than C, initial weight loss, restored in C, was never recovered in S. Fecal excretion exceeded dietary intake by -3.7% in S and reflected absorption and retention of 8.4% dietary Ca in C. Urinary Ca was the same fraction of dietary intake in S and C (9.0 vs 8.6%, NS). Serum Ca, Pi, parathyroid hormone and 1,25-dihydroxyvitamin D were the same in both groups after 28 days. In contrast to the human, a major determinant of negative Ca balance in the mature rat exposed to a space flight model appears to be losses from gastrointestinal Ca secretion, rather than urinary Ca excretion.

Arnaud, Sara B.↗
NASA NTRS2002

Effects of exposure to 56Fe particles or protons on fixed-ratio operant responding in rats

On long-duration trips outside of the magnetosphere, astronauts will be exposed to protons and to heavy particles which can affect their performance of required tasks. It is essential to determine the range of behaviors that might be affected by exposure to these types of radiation in order to understand the nature of behavioral deficits and to develop effective countermeasures. The present experiment examined the ability of rats to make an operant response following exposure to protons (250 MeV, 4 Gy) or 56Fe particles (1 GeV/n, 1 or 2 Gy). Following irradiation, rats were trained to press a lever in order to obtain food reinforcement. They were then placed on an ascending fixed-ratio schedule from FR-1 (each lever press rewarded with a food pellet) through FR-35 (35 lever presses required for 1 food pellet). Rats exposed to 4 Gy of protons or 1 Gy of 56Fe particles responded similarly to controls, increasing their rate of responding as the ratio increased. However, rats exposed to 2 Gy of 56Fe particles failed to increase their rate of responding at ratios greater than FR-20, indicating that rats exposed to 2 Gy of 56Fe particles cannot respond appropriately to increasing work requirements.

Non-NASA Center↗
NASA NTRS2002

Effects of heavy particle irradiation and diet on amphetamine- and lithium chloride-induced taste avoidance learning in rats

Rats were maintained on diets containing either 2% blueberry or strawberry extract or a control diet for 8 weeks prior to being exposed to 1.5 Gy of 56Fe particles in the Alternating Gradient Synchrotron at Brookhaven National Laboratory. Three days following irradiation, the rats were tested for the effects of irradiation on the acquisition of an amphetamine- or lithium chloride-induced (LiCl) conditioned taste avoidance (CTA). The rats maintained on the control diet failed to show the acquisition of a CTA following injection of amphetamine. In contrast, the rats maintained on antioxidant diets (strawberry or blueberry extract) continued to show the development of an amphetamine-induced CTA following exposure to 56Fe particles. Neither irradiation nor diet had an effect on the acquisition of a LiCl-induced CTA. The results are interpreted as indicating that oxidative stress following exposure to 56Fe particles may be responsible for the disruption of the dopamine-mediated amphetamine-induced CTA in rats fed control diets; and that a reduction in oxidative stress produced by the antioxidant diets functions to reinstate the dopamine-mediated CTA. The failure of either irradiation or diet to influence LiCl-induced responding suggests that oxidative stress may not be involved in CTA learning following injection of LiCl.

Non-NASA Center↗
NASA NTRS1998

Maintenance of myonuclear domain size in rat soleus after overload and growth hormone/IGF-I treatment

The purpose of this study was to determine the effects of functional overload (FO) combined with growth hormone/insulin-like growth factor I (GH/IGF-I) administration on myonuclear number and domain size in rat soleus muscle fibers. Adult female rats underwent bilateral ablation of the plantaris and gastrocnemius muscles and, after 7 days of recovery, were injected three times daily for 14 days with GH/IGF-I (1 mg/kg each; FO + GH/IGF-I group) or saline vehicle (FO group). Intact rats receiving saline vehicle served as controls (Con group). Muscle wet weight was 32% greater in the FO than in the Con group: 162 +/- 8 vs. 123 +/- 16 mg. Muscle weight in the FO + GH/IGF-I group (196 +/- 14 mg) was 59 and 21% larger than in the Con and FO groups, respectively. Mean soleus fiber cross-sectional area of the FO + GH/IGF-I group (2,826 +/- 445 microm2) was increased compared with the Con (2,044 +/- 108 microm2) and FO (2,267 +/- 301 microm2) groups. The difference in fiber size between the FO and Con groups was not significant. Mean myonuclear number increased in FO (187 +/- 15 myonuclei/mm) and FO + GH/IGF-I (217 +/- 23 myonuclei/mm) rats compared with Con (155 +/- 12 myonuclei/mm) rats, although the difference between FO and FO + GH/IGF-I animals was not significant. The mean cytoplasmic volume per myonucleus (myonuclear domain) was similar across groups. These results demonstrate that the larger mean muscle weight and fiber cross-sectional area occurred when FO was combined with GH/IGF-I administration and that myonuclear number increased concomitantly with fiber volume. Thus there appears to be some mechanism(s) that maintains the myonuclear domain when a fiber hypertrophies.

NASA Discipline Musculoskeletal↗
NASA NTRS1996

Effects of spaceflight on rat peripheral blood leukocytes and bone marrow progenitor cells

The white blood cell (WBC) elements and the bone marrow myeloid progenitor cell populations were analyzed to ascertain adaptation to micro-gravity and subsequent readaptation to 1 G in rats flown on the 14-day Spacelab Life Sciences-2 (SLS-2) mission. Bone marrow cells were harvested from one group of rats killed inflight (FD13) and blood was drawn from three other groups at various times. The WBC level was normal on FD14 with the exception of neutrophilia. On FD13, numbers of colony-forming units-granulocyte (CFU-G), CFU-GM, and CFU-M from flight animals were decreased compared with ground controls when incubated with recombinant rat interleukin-3 (rrIL-3) alone or in combination with recombinant human erythropoietin (rhEpo). On recovery (R + 0), flight rats had decreased numbers of total leukocytes and absolute numbers of lymphocytes and monocytes with elevated neutrophils compared with control rats. They had lower numbers of CD4, CD8, CD2, CD3, and B cells in the peripheral blood but no differences in spleen lymphocytes.

NASA Discipline Number 00-00↗
NASA NTRS1995

Human parathyroid hormone-(1-38) restores cancellous bone to the immobilized, osteopenic proximal tibial metaphysis in rats

The purpose of this study was to determine if human parathyroid hormone-(1-38) (hPTH(1-38)) can restore cancellous bone mass to the established osteopenic, immobilized proximal tibial metaphyses of female rats. The right hindlimbs of 6-month-old female Sprague-Dawley rats were immobilized by bandaging the right hindlimbs to the abdomen. After 30 days of right hindlimb immobilization, the rats were subcutaneously injected with 200 micrograms hPTH(1-38)/kg/day for 15 days (short-term treatment) or 75 days (longer-term treatment). Static bone histomorphometry was performed on the primary spongiosa, and both static and dynamic histomorphometry were performed on the secondary spongiosa of the right proximal tibial metaphyses. Immobilization for 30 days without treatment decreased trabecular bone area, number, and thickness in both primary and secondary spongiosa, and induced an increase in eroded perimeter and a decrease in tissue referent-bone formation rate in the secondary spongiosa. These changes reached a new steady state thereafter. Treatment with 200 micrograms hPTH(1-38)/kg/day for 15 days, beginning 30 days after immobilization, significantly increased trabecular bone area, thickness, and number in both primary and secondary spongiosa despite continuous immobilization when compared with controls. The short-term PTH treatment (15 days) significantly increased labeling perimeter, mineral apposition rate, and tissue referent-bone formation rate in the secondary spongiosa and stimulated longitudinal bone growth as compared with the controls. Longer PTH treatment (75 days) further increased trabecular bone area, thickness, and number as compared with controls and groups given short-term PTH treatment (15 days). The bone formation indices in the secondary spongiosa of the longer-term treated rats were lower than those of the short-term treated group, but they were still higher than those of controls. Our findings indicate that PTH treatment stimulates cancellous bone formation, and restores and adds extra cancellous bone to the established, disuse-osteopenic proximal tibial metaphysis of female rats with continuously immobilized right hindlimbs. These results suggest that PTH may be useful in treating disuse-induced osteoporosis in humans.

NASA Program Space Physiology and Countermeasures↗
DOE OSTI2022

Susceptibility weighted MRI pinpoints spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats

Purpose: To find magnetic resonance imaging (MRI) precursors of spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats (SHRSP). Method: SHRSP rats were used with both a low/high salt (n = 18 or 11) Japanese diet and salty drinking water to generate spontaneous intracerebral hemorrhage (ICH). Various MRI sequences, and in particular, susceptibility weighted imaging (SWI), were used and combined with a gadolinium (Gd) contrast agent or oxygen gas to identify the rupture of the blood brain barrier (BBB) and the temporal ICH. Results: Most rats developed hypertensive ICH stroke in the high salt group during the 10–13 week period compared to only one third of rats in the low salt group during the 14–18 week period. The location of stroke for both the low/high-salt groups was highest in the striatum (58%/43%), followed by the cortex (21%/30%). The edematous enhancement on T2 weighted (T2W) imaging or Gd based T1 weighted (Gd-T1W) imaging due to the ruptured BBB preceded the striatal hemorrhages seen on SWI. The most recent bleeds were observed on temporal SWI or on oxygen-enhanced SWI. The mode of the volume of bleeds was 0.4 mm 3 . A positive correlation between susceptibility x volume and R2* x volume of the bleeds was observed. Conclusions: SHRSP rats with the high salt diet effectively generated a hypertensive hemorrhagic stroke which could be monitored by various MRI sequences. The venous dilation on SWI may precede any abnormality on T2W or Gd-T1W imaging. The edematous enhancement on T2W or Gd-T1W indicated a BBB breakdown that may precede striatal ICH by several days. This suggests the need for immediate treatment to improve outcome if this finding is observed. Here, the use of oxygen with SWI was able to help differentiate old bleeds from very recent bleeds.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1998

Regulation of the collagenase-3 receptor and its role in intracellular ligand processing in rat osteoblastic cells

We have previously described a specific, saturable receptor for rat collagenase-3 in the rat osteosarcoma cell line, UMR 106-01. Binding of rat collagenase-3 to this receptor is coupled to the internalization and eventual degradation of the enzyme and correlates with observed extracellular levels of the enzyme. In this study we have shown that decreased binding, internalization, and degradation of 125I-rat collagenase-3 were observed in cells after 24 h of parathyroid hormone treatment; these activities returned to control values after 48 h and were increased substantially (twice control levels) after 96 h of treatment with the hormone. Subcellular fractionation studies to identify the route of uptake and degradation of collagenase-3 localized intracellular accumulation of 125I-rat collagenase-3 initially in Golgi-associated lysosomes and later in secondary lysosomes. Maximal lysosomal accumulation of the radiolabel and stimulation of general lysosomal activity occurred after 72 h of parathyroid hormone treatment. Preventing fusion of endosomes with lysosomes (by temperature shift, colchicine, or monensin) resulted in no internalized 125I-collagenase-3 in either lysosomal fraction. Treatment of UMR cells with the above agents or ammonium chloride decreased excretion of 125I-labeled degradation products of collagenase-3. These experiments demonstrated that degradation of collagenase-3 required receptor-mediated endocytosis and sequential processing by endosomes and lysosomes. Thus, parathyroid hormone regulates the expression and synthesis of collagenase-3 as well as the abundance and functioning of the collagenase-3 receptor and the intracellular degradation of its ligand. The coordinate changes in the secretion of collagenase-3 and expression of the receptor determine the net abundance of the enzyme in the extracellular space.

NASA Discipline Musculoskeletal↗
NASA NTRS1997

Effect of a growth hormone treatment on bone orthotropic elasticity in dwarf rats

A refinement of the current ultrasonic elasticity technique was used to measure the orthotropic elastic properties of rat cortical bone as well as to quantify changes in elastic properties, density, and porosity of the dwarf rat cortex after a treatment with recombinant human growth hormone (rhGH). The ultrasonic elasticity technique was refined via optimized signal management of high-frequency wave propagation through cubic cortical specimens. Twenty dwarf rats (37 days old) were randomly assigned to two groups (10 rats each). The dwarf rat model (5-10% of normal GH) was given subcutaneous injections of either rhGH or saline over a 14-day treatment period. Density was measured using Archimedes technique. Porosity and other microstructural characteristics were also explored via scanning electron microscopy and image analysis. Statistical tests verified significant decreases in cortical orthotropic Young's (-26.7%) and shear (-16.7%) moduli and density (-2.42%) concomitant with an increase in porosity (+125%) after rhGH treatments to the dwarf model (p < 0.05). A change in material symmetry from orthotropy toward planar isotropy within the radial-circumferential plane after GH treatments was also noted. These results demonstrate some alteration in bone properties at this time interval. Structural implications of these changes throughout physiological loading regimens should be explored.

NASA Discipline Musculoskeletal↗
NASA NTRS1986

Different reactivity to angiotensin II of peripheral and renal arteries in spontaneously hypertensive rats: effect of acute and chronic angiotensin converting enzyme inhibition

We assessed renal blood flow and pressor responses to graded angiotensin II doses in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats ingesting a diet containing 1.6% sodium basally and after acute and chronic angiotensin converting enzyme (ACE) inhibition with captopril. In the basal state the pressor response to angiotensin II was enhanced (P<0.0005) and the renal vascular response was blunted (P<0.005) in SHR compared with WKY rats. After acute captopril administration the pressor response was enhanced in both strains, and the difference between them was maintained, while the renal vascular response was enhanced in both, but more in SHR, so that the renal vascular response in the SHR became larger than in WKY (P<0.0001). Chronic captopril treatment blunted both pressor and renal responses in WKY rats, but only the pressor response in SHR. The renal vessels of SHR seem to be different from those of WKY rats in reaction to exogenous angiotensin II, and in response to both acute administration of captopril (probably acting through blockade of angiotensin II production) and chronic administration of captopril (probably acting mainly through accumulation of kinin or production of prostaglandins).

NASA Discipline Number 21-50↗
NASA NTRS1998

Comparison of soleus muscles from rats exposed to microgravity for 10 versus 14 days

The effects of two different duration space-flights on the extent of atrophy, fiber type composition, and myosin heavy chain (MHC) content of rat soleus muscles were compared. Adult male Fisher rats (n=12) were aboard flight STS-57 and exposed to 10 days of microgravity and adult ovariectomized female Spraque-Dawley rats (n=12) were aboard flight STS-62 for 14 days. Soleus muscles were bilaterally removed from the flight and control animals and frozen for subsequent analyses. Muscle wet weights, fiber types (I, IC, IIC, and IIA), cross-sectional area, and MHC content were determined. Although a significant difference was found between the soleus wet weights of the two ground-based control groups, they were similar with regard to MHC content (ca 90% MHCI and ca 10% MHCIIa) and fiber type composition. Unloading of the muscles caused slow-to-fast transformations which included a decrease in the percentage of type I fibers and MHCI, an increase in fibers classified as type IC, and the expression of two fast myosin heavy chains not found in the control rat soleus muscles (MHCIId and MHCIIb). Although the amount of atrophy (ca 26%) and the extent of slow-to-fast transformation (decrease in the percentage of MHCI from 90% to 82.5%) in the soleus muscles were similar between the two spaceflights, the percentages of the fast MHCs differed. After 14 days of spaceflight, the percentage of MHCIIa was significantly lower and the percentages of MHCIId and MHCIIb were significantly higher than the corresponding MHC content of the soleus muscles from the 10-day animals. Indeed, MHCIId became the predominant fast MHC after 14 days in space. These data suggest fast-to-faster transformations continued during the longer spaceflight.

short duration↗
DOE OSTI2021

Pulmonary ACE2 expression in neonatal and adult rats

Children show a distinct presentation of COVID‐19, characterized by a lower incidence and mild phenotype, but the reason for this is still unknown. The angiotensin‐converting enzyme 2 (ACE2) functions as the primary cell entry receptor for Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and is thought to cause distinct clinical features between children and old people. The primary purpose of this study was to determine whether differences exist in the level of expression and distribution of ACE2 between neonatal and adult rat lungs. The lung tissues from rats of various ages were used to investigate the expression patterns of ACE2. Western blot, immunohistochemistry, and immunofluorescence were used to quantify or identify the localization of ACE2 in rat lungs. ACE2 was homogenously expressed in fewer alveolar type II (AT2) cells in the neonatal lung, with no polarization to the alveolar space and additional expression in pulmonary endothelium when compared to adult rat lungs. These findings suggest that the patterns of ACE2 distribution and cellular localization in rat lungs change with age.

Zhao, Depeng↗
DOE OSTI2020

Mechanoadaptive strain and functional osseointegration of dental implants in rats

Spatiotemporal implant-bone biomechanics and mechanoadaptive strains in peri-implant tissue are poorly understood. Physical and chemical characteristics of an implant-bone complex (IBC) were correlated in three-dimensional space (along the length and around a dental implant) to gather insights into time related integration of the implant with the cortical portion of a jaw bone in a rat. Rats (N = 9) were divided into three experimental groups with three rats per time point; 3-, 11-, and 24-day. All rats were fed crumbled hard pellets mixed with water (soft-food diet) for the first 3 days followed by a hard-food diet with intact hard-food pellets (groups of 11- and 24-day only). Biomechanics of the IBCs harvested from rats at each time point was evaluated by performing mechanical testing in situ in tandem with X-ray imaging. The effect of physical association (contact area) of a loaded implant with adapting peri-implant tissue, and resulting strain within was mapped by using digital volume correlation (DVC) technique. The IBC stiffness at respective time points was correlated with mechanical strain in peri-implant tissue. Results illustrated that IBC stiffness at 11-day was lower than that observed at 3-day. However, at 24-day, IBC stiffness recovered to that which was observed at 3-day. Furthermore, correlative microscopy and spectroscopy illustrated that the lower IBC stiffness was constituted by softer and less mineralized peri-implant tissue that contained varying expressions of osteoconductive elements. Lower IBC stiffness observed at 11-day was constituted by less mineralized peri-implant tissue with osteoconductive elements that included phosphorus (P) which was co-localized with higher expression of zinc (Zn), and lower expression of calcium (Ca). Higher IBC stiffness at 24-day was constituted by mineralized peri-implant tissue with higher expressions of osteoconductive elements including Ca and P, and lower expressions of Zn. These spatiotemporal correlative maps of peri-implant tissue architecture, heterogeneous distribution of mineral density, and elemental colocalization underscore mechanoadaptive physicochemical properties of peri-implant tissue that facilitate functional osseointegration of an implant. These results provided insights into 1) plausible "prescription" of mechanical loads as an osteoinductive "therapeutic dose" to encourage osteoconductive elements in the peri-implant tissue that would facilitate functional osseointegration of the implant; 2) a "critical temporal window" between 3 and 11 days, and perhaps it is this acute phase during which key candidate regenerative molecules can be harnessed to accelerate osseointegration of an implant under load.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Physiological Adaptations to Progressive Endurance Exercise Training in Adult and Aged Rats: Insights from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ~70%–75% VO 2 max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1–2 wk and improvements in maximum run speed and maximal oxygen uptake by 4–8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Type 2 diabetes impairs annulus fibrosus fiber deformation and rotation under disc compression in the University of California Davis type 2 diabetes mellitus (UCD-T2DM) rat model

Abstract Understanding the biomechanical behavior of the intervertebral disc is crucial for studying disease mechanisms and developing tissue engineering strategies for managing disc degeneration. We used synchrotron small-angle X-ray scattering to investigate how changes to collagen behavior contribute to alterations in the disc’s ability to resist compression. Coccygeal motion segments from 6-month-old lean Sprague-Dawley rats ( n=7) and diabetic obese University of California Davis type 2 diabetes mellitus (UCD-T2DM) rats ( n=6, diabetic for 68±7 days) were compressed during simultaneous synchrotron scanning to measure collagen strain at the nanoscale (beamline 7.3.3 of the Advanced Light Source). After compression, the annulus fibrosus was assayed for nonenzymatic cross-links. In discs from lean rats, resistance to compression involved two main energy-dissipation mechanisms at the nanoscale: (1) rotation of the two groups of collagen fibrils forming the annulus fibrosus and (2) straightening (uncrimping) and stretching of the collagen fibrils. In discs from diabetic rats, both mechanisms were significantly impaired. Specifically, diabetes reduced fibril rotation by 31% and reduced collagen fibril strain by 30% (compared to lean discs). The stiffening of collagen fibrils in the discs from diabetic rats was consistent with a 31% higher concentration of nonenzymatic cross-links and with evidence of earlier onset plastic deformations such as fibril sliding and fibril–matrix delamination. These findings suggest that fibril reorientation, stretching, and straightening are key deformation mechanisms that facilitate whole-disc compression, and that type 2 diabetes impairs these efficient and low-energy elastic deformation mechanisms, thereby altering whole-disc behavior and inducing the earlier onset of plastic deformation.

Rosenberg, James L.↗