The oestrous cycle and skeletal muscle atrophy: Investigations in rodent models of muscle loss.

NEW FINDINGS: What is the central question of this study? Is the oestrous cycle affected during disuse atrophies and, if so, how are oestrous cycle changes related to musculoskeletal outcomes? What is the main finding and its importance? Rodent oestrous cycles were altered during disuse atrophy, which was correlated with musculoskeletal outcomes. However, the oestrous cycle did not appear to be changed by Lewis lung carcinoma, which resulted in no differences in muscle size in comparison to healthy control animals. These findings suggest a relationship between the oestrous cycle and muscle size during atrophic pathologies. ABSTRACT: Recent efforts have focused on improving our understanding of female muscle physiology during exposure to muscle atrophic stimuli. A key feature of female rodent physiology is the oestrous cycle. However, it is not known how such stimuli interact with the oestrous cycle to influence muscle health. In this study, we investigated the impact of muscle atrophic stimuli on the oestrous cycle and how these alterations are correlated with musculoskeletal outcomes. A series of experiments were performed in female rodents, including hindlimb unloading (HU), HU followed by 24 h of reloading, HU combined with dexamethasone treatment, and Lewis lung carcinoma. The oestrous cycle phase was assessed throughout each intervention and correlated with musculoskeletal outcomes. Seven or 14 days of HU increased the duration in dioestrus or metoestrus (D/M; low hormones) and was negatively correlated with gastrocnemius mass. Time spent in D/M was also negatively correlated with changes in grip strength and bone density after HU, and with muscle recovery 24 h after the cessation of HU. The addition of dexamethasone strengthened these relationships between time in D/M and reduced musculoskeletal outcomes. However, in animals with Lewis lung carcinoma, oestrous cyclicity did not differ from that of control animals, and time spent in D/M was not correlated with either gastrocnemius mass or tumour burden. In vitro experiments suggested that enhanced protein synthesis induced by estrogen might protect against muscle atrophy. In conclusion, muscle atrophic insults are correlated with changes in the oestrous cycle, which are associated with deterioration in musculoskeletal outcomes. The magnitude of oestrous cycle alterations depends on the atrophic stimuli.

Estimating myofiber cross-sectional area and connective tissue deposition with electrical impedance myography: A study in D2-mdx mice.

INTRODUCTION: Surface electrical impedance myography (sEIM) has the potential for providing information on muscle composition and structure noninvasively. We sought to evaluate its use to predict myofiber size and connective tissue deposition in the D2-mdx model of Duchenne muscular dystrophy (DMD). METHODS: We applied a prediction algorithm, the least absolute shrinkage and selection operator, to select specific EIM measurements obtained with surface and ex vivo EIM data from D2-mdx and wild-type (WT) mice (analyzed together or separately). We assessed myofiber cross-sectional area histologically and hydroxyproline (HP), a surrogate measure for connective tissue content, biochemically. RESULTS: Using WT and D2-mdx impedance values together in the algorithm, sEIM gave average root-mean-square errors (RMSEs) of 26.6% for CSA and 45.8% for HP, which translate into mean errors of ±363 µm2 for a mean CSA of 1365 µm2 and of ±1.44 µg HP/mg muscle for a mean HP content of 3.15 µg HP/mg muscle. Stronger predictions were obtained by analyzing sEIM data from D2-mdx animals alone (RMSEs of 15.3% for CSA and 34.1% for HP content). Predictions made using ex vivo EIM data from D2-mdx animals alone were nearly equivalent to those obtained with sEIM data (RMSE of 16.59% for CSA), and slightly more accurate for HP (RMSE of 26.7%). DISCUSSION: Surface EIM combined with a predictive algorithm can provide estimates of muscle pathology comparable to values obtained using ex vivo EIM, and can be used as a surrogate measure of disease severity and progression and response to therapy.

Predicting myofiber cross-sectional area and triglyceride content with electrical impedance myography: A study in db/db mice.

BACKGROUND: Electrical impedance myography (EIM) provides insight into muscle composition and structure. We sought to evaluate its use in a mouse obesity model characterized by myofiber atrophy. METHODS: We applied a prediction algorithm, ie, the least absolute shrinkage and selection operator (LASSO), to surface, needle array, and ex vivo EIM data from db/db and wild-type mice and assessed myofiber cross-sectional area (CSA) histologically and triglyceride (TG) content biochemically. RESULTS: EIM data from all three modalities provided acceptable predictions of myofiber CSA with average root mean square error (RMSE) of 15% in CSA (ie, ±209 µm2 for a mean CSA of 1439 µm2 ) and TG content with RMSE of 30% in TG content (ie, ±7.3 nmol TG/mg muscle for a mean TG content of 25.4 nmol TG/mg muscle). CONCLUSIONS: EIM combined with a predictive algorithm provides reasonable estimates of myofiber CSA and TG content without the need for biopsy.

Impact of Dyrk1A level on alcohol metabolism.

Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber-DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level.

Adaptation to full weight-bearing following disuse in rats: The impact of biological sex on musculoskeletal recovery.

With the technological advances made to expand space exploration, astronauts will spend extended amounts of time in space before returning to Earth. This situation of unloading and reloading influences human physiology, and readaptation to full weight-bearing may significantly impact astronauts' health. On Earth, similar situations can be observed in patients who are bedridden or suffer from sport-related injuries. However, our knowledge of male physiology far exceeds our knowledge of female's, which creates an important gap that needs to be addressed to understand the sex-based differences regarding musculoskeletal adaptation to unloading and reloading, necessary to preserve health of both sexes. Using a ground-based model of total unloading for 14 days and reloading at full weight-bearing for 7 days rats, we aimed to compare the musculoskeletal adaptations between males and females. Our results reveal the existence of significant differences. Indeed, males experienced bone loss both during the unloading and the reloading period while females did not. During simulated microgravity, males and females showed comparable muscle deconditioning with a significant decline in rear paw grip strength. However, after 7 days of recovery, muscle strength improved. Additionally, sex-based differences in myofiber size existing at baseline are significantly reduced or eliminated following unloading and recovery.

Influence of gonadectomy on muscle health in micro- and partial-gravity environments in rats.

Gonadal hormones, such as testosterone and estradiol, modulate muscle size and strength in males and females. However, the influence of sex hormones on muscle strength in micro- and partial-gravity environments (e.g., the Moon or Mars) is not fully understood. The purpose of this study was to determine the influence of gonadectomy (castration/ovariectomy) on progression of muscle atrophy in both micro- and partial-gravity environments in male and female rats. Male and female Fischer rats (n = 120) underwent castration/ovariectomy (CAST/OVX) or sham surgery (SHAM) at 11 wk of age. After 2 wk of recovery, rats were exposed to hindlimb unloading (0 g), partial weight bearing at 40% of normal loading (0.4 g, Martian gravity), or normal loading (1.0 g) for 28 days. In males, CAST did not exacerbate body weight loss or other metrics of musculoskeletal health. In females, OVX animals tended to have greater body weight loss and greater gastrocnemius loss. Within 7 days of exposure to either microgravity or partial gravity, females had detectable changes to estrous cycle, with greater time spent in low-estradiol phases diestrus and metestrus (∼47% in 1 g vs. 58% in 0 g and 72% in 0.4 g animals, P = 0.005). We conclude that in males testosterone deficiency at the initiation of unloading has little effect on the trajectory of muscle loss. In females, initial low estradiol status may result in greater musculoskeletal losses.NEW & NOTEWORTHY We find that removal of gonadal hormones does not exacerbate muscle loss in males or females during exposure to either simulated microgravity or partial-gravity environments. However, simulated micro- and partial gravity did affect females' estrous cycles, with more time spent in low-estrogen phases. Our findings provide important data on the influence of gonadal hormones on the trajectory of muscle loss during unloading and will help inform NASA for future crewed missions to space and other planets.

Sex differences in muscle health in simulated micro- and partial-gravity environments in rats.

Skeletal muscle size and strength are important for overall health for astronauts. However, how male and female muscle may respond differently to micro- and partial-gravity environments is not fully understood. The purpose of this study was to determine how biological sex and sex steroid hormones influence the progression of muscle atrophy after long term exposure to micro and partial gravity environments in male and female rats. Male and female Fisher rats (n â€‹= â€‹120) underwent either castration/ovariectomy or sham surgeries. After two weeks recovery, animals were divided into microgravity (0g), partial-gravity (40% of weight bearing, 0.4g), or full weight bearing (1g) interventions for 28 days. Measurements of muscle size and strength were evaluated prior to and after interventions. At 0g, females lost more dorsiflexion strength, plantar flexion strength, and other metrics of muscle size compared to males; castration/ovariectomy did not influence these differences. Additionally, at 0.4g, females lost more dorsiflexion strength, plantar flexion strength, and other metrics of muscle strength compared to males; castration/ovariectomy did not influence these differences. Females have greater musculoskeletal aberrations during exposure to both microgravity and partial-gravity environments; these differences are not dependent on the presence of sex steroid hormones. Correspondingly, additional interventions may be necessary to mitigate musculoskeletal loss in female astronauts to protect occupational and overall health.

Skeletal muscle deconditioning during partial weight-bearing in rodents - A systematic review and meta-analysis.

Space agencies are planning to send humans back to the Lunar surface, in preparation for crewed exploration of Mars. However, the effect of hypogravity on human skeletal muscle is largely unknown. A recently established rodent partial weight-bearing model has been employed to mimic various levels of hypogravity loading and may provide valuable insights to better understanding how human muscle might respond to this environment. The aim of this study was to perform a systematic review regarding the effects of partial weight-bearing on the morphology and function of rodent skeletal muscle. Five online databases were searched with the following inclusion criteria: population (rodents), intervention (partial weight-bearing for ≥1 week), control (full weight-bearing), outcome(s) (skeletal muscle morphology/function), and study design (animal intervention). Of the 2,993 studies identified, eight were included. Partial weight-bearing at 20%, 40%, and 70% of full loading caused rapid deconditioning of skeletal muscle morphology and function within the first one to two weeks of exposure. Calf circumference, hindlimb wet muscle mass, myofiber cross-sectional area, front/rear paw grip force, and nerve-stimulated plantarflexion force were reduced typically by medium to very large effects. Higher levels of partial weight-bearing often attenuated deconditioning but failed to entirely prevent it. Species and sex mediated the deconditioning response. Risk of bias was low/unclear for most studies. These findings suggest that there is insufficient stimulus to mitigate muscular deconditioning in hypogravity settings highlighting the need to develop countermeasures for maintaining astronaut/cosmonaut muscular health on the Moon and Mars.

Bone deconditioning during partial weight-bearing in rodents - A systematic review and meta-analysis.

Space agencies are preparing to send humans to the Moon (16% Earth's gravity) and Mars (38% Earth's gravity), however, there is limited evidence regarding the effects of hypogravity on the skeletal system. A novel rodent partial weight-bearing (PWB) model may provide insight into how human bone responds to hypogravity. The aim of this study was to perform a systematic review investigating the effect of PWB on the structure and function of rodent bone. Five online databases were searched with the following inclusion criteria: population (rodents), intervention (PWB for ≥1-week), control (full weight-bearing), outcomes (bone structure/function), and study design (animal intervention). Of the 2,993 studies identified, eight were included. The main findings were that partial weight-bearing exposure for 21-28 days at 20%, 40%, and 70% of full loading causes: (1) loss of bone mineral density, (2) loss of trabecular bone volume, thickness, number, and increased separation, (3) loss of cortical area and thickness, and 4) reduced bone stiffness and strength. These findings predominately relate the tibia/femur of young/mature female mice, however, their deconditioning response appeared similar, but not identical, to male rats. A dose-response trend was frequently observed between the magnitude of deconditioning and PWB level. The deconditioning patterns in PWB resembled those in rodents and humans exposed to microgravity and microgravity analogs. The present findings suggest that countermeasures against bone deconditioning may be required for humans exploring the Lunar and Martian surfaces.

Performing In Vivo and Ex Vivo Electrical Impedance Myography in Rodents.

Electrical impedance myography (EIM) is a convenient technique that can be used in preclinical and clinical studies to assess muscle tissue health and disease. EIM is obtained by applying a low-intensity, directionally focused, electrical current to a muscle of interest across a range of frequencies (i.e., from 1 kHz to 10 MHz) and recording the resulting voltages. From these, several standard impedance components, including the reactance, resistance, and phase, are obtained. When performing ex vivo measurements on excised muscle, the inherent passive electrical properties of the tissue, namely the conductivity and relative permittivity, can also be calculated. EIM has been used extensively in animals and humans to diagnose and track muscle alterations in a variety of diseases, in relation to simple disuse atrophy, or as a measure of therapeutic intervention. Clinically, EIM offers the potential to track disease progression over time and to assess the impact of therapeutic interventions, thus offering the opportunity to shorten the clinical trial duration and reduce sample size requirements. Because it can be performed noninvasively or minimally invasively in living animal models as well as humans, EIM offers the potential to serve as a novel translational tool enabling both preclinical and clinical development. This article provides step-by-step instructions on how to perform in vivo and ex vivo EIM measurements in mice and rats, including approaches to adapt the techniques to specific conditions, such as for use in pups or obese animals.

Hindlimb suspension in Wistar rats: Sex-based differences in muscle response.

Ground-based animal models have been used extensively to understand the effects of microgravity on various physiological systems. Among them, hindlimb suspension (HLS), developed in 1979 in rats, remains the gold-standard and allows researchers to study the consequences of total unloading of the hind limbs while inducing a cephalic fluid shift. While this model has already brought valuable insights to space biology, few studies have directly compared functional decrements in the muscles of males and females during HLS. We exposed 28 adult Wistar rats (14 males and 14 females) to 14 days of HLS or normal loading (NL) to better assess how sex impacts disuse-induced muscle deconditioning. Females better maintained muscle function during HLS than males, as shown by a more moderate reduction in grip strength at 7 days (males: -37.5 ± 3.1%, females: -22.4 ± 6.5%, compared to baseline), that remains stable during the second week of unloading (males: -53.3 ± 5.7%, females: -22.4 ± 5.5%, compared to day 0) while the males exhibit a steady decrease over time (effect of sex × loading p = 0.0002, effect of sex × time × loading p = 0.0099). This was further supported by analyzing the force production in response to a tetanic stimulus. Further functional analyses using force production were also shown to correspond to sex differences in relative loss of muscle mass and CSA. Moreover, our functional data were supported by histomorphometric analyzes, and we highlighted differences in relative muscle loss and CSA. Specifically, female rats seem to experience a lesser muscle deconditioning during disuse than males thus emphasizing the need for more studies that will assess male and female animals concomitantly to develop tailored, effective countermeasures for all astronauts.

The individual and combined effects of spaceflight radiation and microgravity on biologic systems and functional outcomes.

Both microgravity and radiation exposure in the spaceflight environment have been identified as hazards to astronaut health and performance. Substantial study has been focused on understanding the biology and risks associated with prolonged exposure to microgravity, and the hazards presented by radiation from galactic cosmic rays (GCR) and solar particle events (SPEs) outside of low earth orbit (LEO). To date, the majority of the ground-based analogues (e.g., rodent or cell culture studies) that investigate the biology of and risks associated with spaceflight hazards will focus on an individual hazard in isolation. However, astronauts will face these challenges simultaneously Combined hazard studies are necessary for understanding the risks astronauts face as they travel outside of LEO, and are also critical for countermeasure development. The focus of this review is to describe biologic and functional outcomes from ground-based analogue models for microgravity and radiation, specifically highlighting the combined effects of radiation and reduced weight-bearing from rodent ground-based tail suspension via hind limb unloading (HLU) and partial weight-bearing (PWB) models, although in vitro and spaceflight results are discussed as appropriate. The review focuses on the skeletal, ocular, central nervous system (CNS), cardiovascular, and stem cells responses.

Approaching Gravity as a Continuum Using the Rat Partial Weight-Bearing Model.

For decades, scientists have relied on animals to understand the risks and consequences of space travel. Animals remain key to study the physiological alterations during spaceflight and provide crucial information about microgravity-induced changes. While spaceflights may appear common, they remain costly and, coupled with limited cargo areas, do not allow for large sample sizes onboard. In 1979, a model of hindlimb unloading (HU) was successfully created to mimic microgravity and has been used extensively since its creation. Four decades later, the first model of mouse partial weight-bearing (PWB) was developed, aiming at mimicking partial gravity environments. Return to the Lunar surface for astronauts is now imminent and prompted the need for an animal model closer to human physiology; hence in 2018, our laboratory created a new model of PWB for adult rats. In this review, we will focus on the rat model of PWB, from its conception to the current state of knowledge. Additionally, we will address how this new model, used in conjunction with HU, will help implement new paradigms allowing scientists to anticipate the physiological alterations and needs of astronauts. Finally, we will discuss the outstanding questions and future perspectives in space research and propose potential solutions using the rat PWB model.

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

[This corrects the article DOI: 10.3389/fphys.2020.00302.].

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

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.

Dose-dependent skeletal deficits due to varied reductions in mechanical loading in rats.

Reduced skeletal loading leads to marked bone loss. Animal models of hindlimb suspension are widely used to assess alterations in skeleton during the course of complete unloading. More recently, the effects of partial unloading on the musculoskeletal system have been interrogated in mice and rats, revealing dose-dependent effects of partial weight bearing (PWB) on the skeleton and skeletal muscle. Here, we extended these studies to determine the structural and functional skeletal alterations in 14-week-old male Wister rats exposed to 20%, 40%, 70%, or 100% of body weight for 1, 2, or 4 weeks (n = 11-12/group). Using in vivo pQCT, we found that trabecular bone density at the proximal tibia declined in proportion to the degree of unloading and continued progressively with time, without evidence of a plateau by 4 weeks. Ex vivo measurements of trabecular microarchitecture in the distal femur by microcomputed tomography revealed deficits in bone volume fraction, 2 and 4 weeks after unloading. Histologic analyses of trabecular bone in the distal femur revealed the decreased osteoblast number and mineralizing surface in unloaded rats. Three-point bending of the femoral diaphysis indicated modest or no reductions in femoral stiffness and estimated modulus due to PWB. Our results suggest that this rat model of PWB leads to trabecular bone deterioration that is progressive and generally proportional to the degree of PWB, with minimal effects on cortical bone.

Using Electrical Impedance Myography as a Biomarker of Muscle Deconditioning in Rats Exposed to Micro- and Partial-Gravity Analogs.

As astronauts prepare to undertake new extra-terrestrial missions, innovative diagnostic tools are needed to better assess muscle deconditioning during periods of weightlessness and partial gravity. Electrical impedance myography (EIM) has been used to detect muscle deconditioning in rodents exposed to microgravity during spaceflight or using the standard ground-based model of hindlimb unloading via tail suspension (HU). Here, we used EIM to assess muscle changes in animals exposed to two new models: hindlimb suspension using a pelvic harness (HLS) and a partial weight-bearing (PWB) model that mimics partial gravity (including Lunar and Martian gravities). We also used a simple needle array electrode in lieu of surface or ex vivo EIM approaches previously employed. Our HLS results confirmed earlier findings obtained after spaceflight and tail suspension. Indeed, one EIM measure (i.e., phase-slope) that was previously reported as highly sensitive, was significantly decreased after HLS (day 0: 14.60 ± 0.97, day 7: 11.03 ± 0.81, and day 14: 10.13 ± 0.55 | Deg/MHz|, p < 0.0001), and was associated with a significant decrease in muscle grip force. Although EIM parameters such as 50 kHz phase, reactance, and resistance remained variable over 14 days in PWB animals, we identified major PWB-dependent effects at 7 days. Moreover, the data at both 7 and 14 days correlated to previously observed changes in rear paw grip force using the same PWB model. In conclusion, our data suggest that EIM has the potential to serve as biomarker of muscle deconditioning during exposure to both micro- and partial- gravity during future human space exploration.

Circulating miRNA Spaceflight Signature Reveals Targets for Countermeasure Development.

We have identified and validated a spaceflight-associated microRNA (miRNA) signature that is shared by rodents and humans in response to simulated, short-duration and long-duration spaceflight. Previous studies have identified miRNAs that regulate rodent responses to spaceflight in low-Earth orbit, and we have confirmed the expression of these proposed spaceflight-associated miRNAs in rodents reacting to simulated spaceflight conditions. Moreover, astronaut samples from the NASA Twins Study confirmed these expression signatures in miRNA sequencing, single-cell RNA sequencing (scRNA-seq), and single-cell assay for transposase accessible chromatin (scATAC-seq) data. Additionally, a subset of these miRNAs (miR-125, miR-16, and let-7a) was found to regulate vascular damage caused by simulated deep space radiation. To demonstrate the physiological relevance of key spaceflight-associated miRNAs, we utilized antagomirs to inhibit their expression and successfully rescue simulated deep-space-radiation-mediated damage in human 3D vascular constructs.

A Moderate Daily Dose of Resveratrol Mitigates Muscle Deconditioning in a Martian Gravity Analog.

While there is a relatively good understanding of the effects of microgravity on human physiology based on five decades of experience, the physiological consequences of partial gravity remain far less well understood. Until recently, no model had been able to replicate partial gravity such as that experienced on Mars (0.38 g), which would be critical to help sustain long-term missions and ensure a safe return to Earth. Recent development of two partial weight bearing (PWB) models, one in mice and one in rats, now allows for quadrupedal partial unloading that mimics Martian gravity. Resveratrol (RSV), a polyphenol most commonly found in grapes and blueberries, has been extensively investigated for its health benefits, including its anti-inflammatory, anti-oxidative, and anti-diabetic effects. In the context of mechanical unloading, RSV has also been shown to preserve bone and muscle mass. However, there is a lack of research regarding its effect on the musculoskeletal system in partial gravity. We hypothesized that a moderate daily dose of RSV (150 mg/kg/day) would help mitigate muscle deconditioning in a Mars gravity analog. Indeed, our results demonstrate that RSV treatment during partial unloading significantly preserves muscle function (e.g., the average change in grip force after 14 days of PWB40 was of -6.18, and +10.92% when RSV was administered) and mitigates muscle atrophy (e.g., RSV supplementation led to an increase of 21.6% in soleus weight for the unloaded animals). This work suggests the potential of a nutraceutical approach to reduce musculoskeletal deconditioning on a long-term mission to Mars.

Mimicking a Space Mission to Mars Using Hindlimb Unloading and Partial Weight Bearing in Rats.

Rodent ground-based models are widely used to understand the physiological consequences of space flight on the physiological system and have been routinely employed since 1979 and the development of hind limb unloading (HLU). However, the next steps in space exploration now include to travel to Mars where the gravity is 38% of Earth's gravity. Since no human being has experienced this level of partial gravity, a sustainable ground-based model is necessary to investigate how the body, already impaired by the time spent in microgravity, would react to this partial load. Here, we used our innovative partial weight-bearing (PWB) model to mimic a short mission and stay on Mars to assess the physiological impairments in the hind limb muscles induced by two different levels of reduced gravity applied in sequential fashion. This could provide a safe, ground-based model to study the musculoskeletal adaptations to gravitational change and to establish effective countermeasures to preserve astronauts' health and function.