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Partial Weight-Bearing in Female Rats: Proof of Concept in a Martian-Gravity Analog.

ABSTRACT: Many studies have investigated the physiological response to microgravity in both astronauts and animals. However, while space agencies have sought to deploy more women on their missions; animal models rarely include females studies or comparisons between males and females. Therefore, we exposed adult female rats to 2 weeks of partial weight-bearing at either 100% of their normal loading (PWB100) or 40% of their normal loading (PWB40), corresponding to Martian gravity-analog, and assess muscle function, force and histomorphometry. Females exposed to PWB showed an 11.62% decline in hindlimb grip force associated with an 11.84% decrease in soleus myofiber size after 14 days of exposure, while maintaining normal blood oxygenation and stress levels. This pilot study represents the first experiment designed to understand the muscular disuse associated with a partial reduction in mechanical loading in female rats, and the first step needed to develop successful mitigating strategies. New and Noteworthy:This research article describes the first use of quadrupedal partial weight-bearing in female rats. This study demonstrates the feasibility of partial gravity analogs in females and allows for future investigations about the impact of sex on muscle deconditioning due to reduced mechanical loading.

SUBMITTER: Semple C

PROVIDER: S-EPMC7145975 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Partial Weight-Bearing in Female Rats: Proof of Concept in a Martian-Gravity Analog.

Semple Carson C Riveros Daniela D Nagy Janice A JA Rutkove Seward B SB Mortreux Marie M

Frontiers in physiology 20200403

Many studies have investigated the physiological response to microgravity in both astronauts and animals. However, while space agencies have sought to deploy more women on their missions; animal models rarely include females studies or comparisons between males and females. Therefore, we exposed adult female rats to 2 weeks of partial weight-bearing at either 100% of their normal loading (PWB100) or 40% of their normal loading (PWB40), corresponding to Martian gravity-analog, and assess muscle f ...[more]

PMID: 32308630

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Project description:The return to the Moon and the landing on Mars has emphasized the need for greater attention to the effects of partial gravity on human health. Here, we sought to devise a new type of simulated partial gravity apparatus that could more efficiently and accurately provide a partial gravity environment for rat hindlimbs. The new apparatus uses a pulley system and tail suspension to create the simulated partial gravity of the rat's hind limbs by varying the weight in a balance container attached to the pulley system. An experiment was designed to verify the reliability and stability of the new apparatus. In this experiment, 25 seven-week-old male Wistar Hannover rats were randomly divided into five groups (n = 5 per group): hindlimb full weight-bearing control (1G), sham (1G), and the simulated gravity groups including Mars (3/8G), Moon (1/6G), and interplanetary space (microgravity: µG). The levels of partial gravity experienced by rat hindlimbs in the Mars and Moon groups were provided by a novel simulated partial gravity device. Changes in bone parameters [overall bone mineral density (BMD), trabecular BMD, cortical BMD, cortical bone thickness, minimum moment of area (MMA), and polar moment of area (PMA)] were evaluated using computed tomography in all rats at the proximal, middle, and distal regions of femur and tibia. Reduced gravity led to decreases in bone parameters (overall BMD, trabecular BMD, cortical BMD, MMA, and PMA) in the simulated gravity groups, mainly in distal femur and proximal tibia. The proximal tibia, MMA, and PMA findings indicated greater weakness in the µG group than in the Mars group. The sham group design also excluded the decrease in lower limb bone parameters caused by the suspension attachment of the rat's tail. The new simulated partial gravity apparatus can provide a continuous and stable level of partial gravity. It offers a reliable and valuable model for studying the effects of extraterrestrial gravity environments on humans.

Project description:UNLABELLED:Intraarterial microdosing (IAM) is a novel drug development approach combining intraarterial drug delivery and microdosing. We aimed to demonstrate that IAM leads to target exposure similar to that of systemic full-dose administration but with minimal systemic exposure. IAM could enable the safe, inexpensive, and early study of novel drugs at the first-in-human stage and the study of established drugs in vulnerable populations. METHODS:Insulin was administered intraarterially (ipsilateral femoral artery) or systemically to 8 CD IGS rats just before blood sampling or 60-min (18)F-FDG uptake PET imaging of ipsilateral and contralateral leg muscles (lateral gastrocnemius) and systemic muscles (spinotrapezius). The (18)F-FDG uptake slope analysis was used to compare the interventions. Plasma levels of insulin and glucose were compared using area under the curve calculated by the linear trapezoidal method. A physiologically based computational pharmacokinetics/pharmacodynamics model was constructed to simulate the relationship between the administered dose and response over time. RESULTS:(18)F-FDG slope analysis found no difference between IAM and systemic full-dose slopes (0.0066 and 0.0061, respectively; 95% confidence interval [CI], -0.024 to 0.029; P = 0.7895), but IAM slope was statistically significantly greater than systemic microdose (0.0018; 95% CI, -0.045 to -0.007; P = 0.0147) and sham intervention (-0.0015; 95% CI, 0.023-0.058; P = 0.0052). The pharmacokinetics/pharmacodynamics data were used to identify model parameters that describe membrane insulin binding and glucose-insulin dynamics. CONCLUSION:Target exposure after IAM was similar to systemic full dose administration but with minimal systemic effects. The computational pharmacokinetics/pharmacodynamics model can be generalized to predict whole-body response. Findings should be validated in larger, controlled studies in animals and humans using a range of targets and classes of drugs.

Dataset Information

Partial Weight-Bearing in Female Rats: Proof of Concept in a Martian-Gravity Analog.

Publications

Partial Weight-Bearing in Female Rats: Proof of Concept in a Martian-Gravity Analog.

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