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J Appl Physiol 86: 1841-1846, 1999;
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Vol. 86, Issue 6, 1841-1846, June 1999

Reversal of weightlessness-induced musculoskeletal losses with androgens: quantification by MRI

Sunishka M. Wimalawansa1, Maria T. Chapa1, Jingna N. Wei2, Karin N. Westlund2, Michael J. Quast2, and Sunil J. Wimalawansa1

Departments of 1 Internal Medicine and 2 Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, Texas 77555-1065.


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Microgravity causes rapid decrement in musculoskeletal mass is associated with a marked decrease in circulatory testosterone levels, as we reported in hindlimb-suspended (HLS) rats. In this model which simulates microgravity, we hypothesized that testosterone supplementation should prevent these losses, and we tested this in two studies. Muscle volumes and bone masses were quantitated by using magnetic resonance imaging (MRI) on day 12. In the first study, 12-wk-old Sprague-Dawley rats that were HLS for 12 days lost 28.5% of muscle volume (53.3 ± 4.8 vs. 74.5 ± 3.6 cm3 in the ground control rats; P < 0.001) and had a 5% decrease in bone mineral density (BMD) (P < 0.05). In the second study, 30 male 12-wk-old Wistar rats were HLS and were administered either a vehicle (control), testosterone, or nandrolone decanoate (ND). An additional 20 rats were used as ground controls, one-half of which received testosterone. HLS rats had a significant reduction in muscle volume (42.9 ± 3.0 vs. 56 ± 1.8 cm3 in ground control rats; P < 0.01). Both testosterone and ND treatments prevented this muscle loss (51.5 ± 2 and 51.6 ± 1.2 cm3, respectively; a 63% improvement; P < 0.05). There were no statistical differences between the two active treatment groups nor with the ground controls. Similarly, there was an 85% improvement in BMD in the testosterone group (1.15 ± 0.04 vs. 1.04 ± 0.04 density units in vehicle controls; P < 0.05) and a 76% improvement in the ND group (1.13 ± 0.07 density units), whereas ground control rats had a BMD of 1.17 ± 0.03 density units. Because serum testosterone levels are markedly reduced in this model of simulated microgravity, androgen replacement seems to be a rational countermeasure to prevent microgravity-induced musculoskeletal losses.

osteoporosis; microgravity; bone turnover; bone mineral density; anabolic steriod; disuse atrophy


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

DECREMENTS IN BONE AND MUSCLE mass are major concerns in extended space missions (1, 8, 9, 38, 49). Immobilization (e.g., bed rest or restricted movements of limbs) can also cause rapid losses in muscle or bone mass (6, 9, 25, 26). Immobilization, prolonged bed rest, and spaceflight conditions inducing microgravity conditions can lead to the general or selective loss of muscle volume and mass. In addition, these conditions lead to negative calcium balance and loss of bone mineral density (BMD) (11, 13, 32, 33). A similar reduction in musculoskeletal mass has been reported due to the immobilization of extremities seen in external bandaging, casting, or neural resectioning (13, 25, 27, 39-43). Both mineralization and collagen metabolism seem to be impaired in animals during the first few days of spaceflight (34). Urine analysis in Skylab astronauts has shown a significant loss of minerals, including calcium (10, 37). Reduction of muscle forces leads to a decrease in bone formation and BMD in the os calcis and an increase in urinary loss of calcium but no loss of BMD in the radius and ulna in Skylab crew members after an 84-day orbital flight (36). Bone mineral losses during tail suspension or spaceflights are more prevalent in weight-bearing bones and are due mainly to a decrease in bone formation (19, 29, 49).

It has also been reported that mechanical unloading may also account for the differential loss in skeletal muscle mass and volume of mice and rats observed during spaceflights. For example, the weight of the soleus and extensor digitorum longus muscles decreased significantly during the Cosmos 605 flight (18, 24), whereas such weight changes were not observed in the biceps brachii and diaphragm muscles. Over the past few years, several countermeasures have been examined to prevent the loss of musculoskeletal mass during exposure to microgravity. These include pharmacological therapies, such as calcitonin and bisphosphonates, and several active and passive exercise regimens, but the outcomes have been limited.

The hindlimb-elevation model in rats has been shown to simulate the bone turnover and muscle changes seen in growing rats in spaceflight (18, 19, 34). This model mimics the effects of microgravity on musculoskeletal systems, metabolic changes affecting bone formation, renal function, electrolyte disturbances, and muscle mass as compared with those recorded from biosatellite animals. Our laboratory (45, 47) and others (30, 48) previously demonstrated that there is a significant decrease in serum testosterone levels in tail-suspended rats and that this is probably independent of the changes in serum cortisol levels. We hypothesized that this marked decrease in testosterone levels contributes, at least in part, to the observed decrement in musculoskeletal mass. Testosterone, as well as the synthetic anabolic androgen analog, nandrolone decanoate (ND), has also been shown to decrease bone turnover and increase BMD in animals and humans (21, 40). Therefore, this study was designed to assess whether hindlimb-suspension-induced reduction in musculoskeletal mass can be prevented with testosterone or ND.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Protocol

In this study we used a well-established animal model of hindlimb suspension (i.e., tail-suspended rat) to simulate microgravity conditions (11, 33, 50). In the first study, 14 weight-matched 12-wk-old male Sprague-Dawley rats and, in the second study, 40 weight-matched 12 wk-old male Wistar rats (Charles River, Wilmington, WA) were used. They were individually housed in cages specially designed for tail suspension. Rats were fed standard chow (Purina rat chow; Purina Mills, St. Louis, MO) containing 1.01% calcium and 0.74% phosphorus and were maintained at 74°F on a 12:12-h light-dark cycle.

Unlike humans and monkeys, in adult rats, mice, and rabbits, the inguinal canal remains open. Furthermore, it has been shown that, when male rats and mice are tail suspended (or during spaceflight), their testes periodically move into the abdominal cavity. Because of the increased temperature in this new environment, the testes undergo several changes, including dramatic reduction in spermatogenesis (20). Marked changes occur in the histology of the testis and epididymis in tail-suspended rats without inguinal canal ligation (5, 16). Therefore, in the present study after a short period of acclimatization in the animal care facility in both control and tail-suspended rats under anesthesia, a loose ligature of nonabsorbable suture was placed around the inguinal canal to prevent the testes from moving into the abdominal cavity. Precautions were taken to make sure that the spermatic cords were not occluded and the ligatures were sufficiently loose for testicular growth.

Tail Suspension

Animals were hindlimb suspended (HLS), with slight modification to the method previously described (48). Briefly, the tails were cleaned with 70% alcohol and swabbed with a tincture of benzoin; a strip of moleskin orthopedic adhesive tape (Johnson and Johnson, Arlington, TX) 1 cm wide was run from the base to two-thirds of the way up on one side of the tail. A small loop was formed at the top through which a paper clip was inserted, and then the tape was continued back down the opposite side of the tail. The tail tip was free of adhesive tape, and blood sampling was done at this site. A strip of gauze was loosely spiraled up the tail, and the two ends were secured with adhesive medical tape. Care was taken not to wrap the tape too tightly, and tails were examined three times a day throughout the experimental period to ensure that circulation was intact and maintained. The paper clip attached to the loop was used to suspend the rats from a chain attached to a suspension apparatus. The chain allowed adjustments in hindlimb-suspension height to maintain a 30° head-down tilt that maintained normal loading on the forelimbs. The suspension apparatus allowed the animals free access to food and water and unrestricted movements of their forelimbs.

The apparatus consisted of an L-shaped metal strip bolted to the rear of the cage, and a long arm projecting 30 cm toward the cage center. A rotating piece attached to the arm allowed 360° swivel suspension from the free end and prevented rats from climbing onto the cage walls. The tails of the ground-control animals were also taped as described above (but without a loop at the tail end), and the rats were housed singly and unrestricted in identical cages. Even transient loading after weightlessness can alter musculoskeletal tissue biochemistry and change the local tissue levels of cytokines (24). Therefore, to minimize changes in the musculoskeletal system, only one rat at a time was removed from the suspension for weighing and also for magnetic resonance imaging (MRI) scanning. Remaining rats were left tail suspended. The experimental protocol was approved by the Animal Care and Use Committee at The University of Texas Medical Branch at Galveston, and the animals were maintained in accordance with NIH Guidelines for the Care and Use of Laboratory Animals.

MRI of Muscle and Bone

On day 12, the rats were removed from suspension, anesthetized, and subjected to MRI (16). Proton MRI was performed by using a 4.7-T 33-cm-bore magnet (SISCO/Varian, Palo Alto, CA). MRI scans were acquired with a square field of view of 10 cm and 128 phase-encode steps and were reconstructed by using one 256 × 256 matrix, which translated to an in-plane resolution of 0.39 mm/pixel. Thirty contiguous coronal slices were acquired, covering a 2-cm length from the tip of the pelvis, with a slice thickness of 1.7 mm. Repetition time was 3.0 s, and echo time was 30 ms. The muscle volumes were calculated from the area of each slice multiplied by the slice thickness and summed to yield the total volume in cubic centimeters. Muscle volumes were determined at the quadriceps muscle on the right leg, and the bone density was measured in the right femur and is expressed in density units (29, 36, 45, 49, 51). Figure 1 illustrates comparison MRI images of a HLS rat treated with the vehicle vs. a HLS rat treated with testosterone.


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  		Fig. 1.   Magnetic resonance images (MRI) of muscles and bones of tail-suspended rats. A: control tail-suspended rat; B: tail-suspended rat treated with testosterone. Arrows indicate site of muscle atrophy.

Study 1. After a week of postsurgical observation, seven rats were suspended from the tail (hindlimbs well above the base of the cage), and the remaining seven rats were used as ground controls. Each weight-bearing group was fed the average daily amount of food consumed by its corresponding tail-suspended group of rats (i.e., pair fed). The rats were weighed every third day to ensure weight maintenance, as stable normal body weight is considered to be a reliable index of an animal's ability to tolerate stressful conditions (49). Muscle volume and BMD were measured on day 12 in both control and tail-suspended rats under ketamine anesthesia.

Study 2. Thirty rats were assigned to three groups and were tail-suspended, while an additional 20 rats were used as ground controls. All tail-suspended rats received either a single intramuscular injection of vehicle (sesame oil, placebo, 100 µl), depot testosterone (6 mg/kg body wt), or ND (6 mg/kg body wt) at the beginning of the experiment. While 10 ground-control rats received a vehicle injection, testosterone (6 mg/kg body wt) was administered to the remaining 10 ground-control rats. The rats were weighed every third day to ensure weight maintenance. On the 12th day, the rats were anesthetized and subjected to MRI scanning of the quadriceps muscle and bone density in the femur.

Statistics

Statistical analysis was performed by using the SigmaStat statistical package (Jandel, San Rafael, CA). Differences between groups were analyzed by analysis of variance, followed by the Student-Newman-Keuls test for multiple-group comparisons. Between-group data were also evaluated first by Kruskal-Wallis one-way analysis to determine whether differences existed, and then by Newman-Keuls multiple-group comparison test to determine whether the groups varied significantly from each other. A value of P < 0.05 was considered to be a significant effect.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study 1

The body weights of the tail-suspended rats (at the beginning and after 12 days of suspension) were not statistically different from those of the non-tail-suspended control-group rats (266 ± 2 and 272 ± 2 g, tail-suspended rats; 268 ± 2 and 280 ± 2 g, ground control rats, respectively). Rats exposed to simulated weightlessness lost 28.5% of muscle volume in the affected hindlimbs as measured with MRI during the 12-day experimental period of tail suspension (53.3 ± 4.8 cm3; P < 0.01) when compared with nonsuspended ground-control rats (74.5 ± 3.6 cm3; Fig. 2A). In addition, there was a 5% decrease (P < 0.05) of BMD in the femur of tail-suspended rats in comparison with the ground controls (Fig. 2B).


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  		Fig. 2.   A: changes (± SE) in muscle volume (cm3) measured by MRI in controls and rats subjected to 12-day tail suspension (n = 7 each group; 28% change). * P < 0.01. B: bone mass in proximal femur measured by MRI in tail-suspended rats compared with controls (n = 7 each group; 5% change). * P < 0.05.

Study 2

The body weights of the three groups of tail-suspended rats at the basal and on day 12 were not statistically different from those of the non-tail-suspended control-group rats. The mean weights of these rats on day 12 were as follows: ground controls, 307 ± 2 g; testosterone-treated ground controls, 310 ± 2 g; tail-suspended untreated controls, 299 ± 2 g; tail-suspended testosterone-treated rats, 305 ± 2 g; and tail-suspended ND-treated rats, 303 ± 2 g. In this study, a significant protection of the musculoskeletal system was seen in the rats treated with both testosterone and ND in comparison with the vehicle-treated group. Tail-suspended rats lost 24% of muscle volume in the affected hindlimbs within the 12-day period of tail suspension (42.9 ± 3.3 vs. 56.5 ± 1.8 cm3 in ground controls; P < 0.01). A 63% reduction in this expected muscle loss was observed after a single injection of testosterone (51.5 ± 2.2 cm3) or ND (51.6 ± 1.2 cm3; P < 0.05; Fig. 3).


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  		Fig. 3.   Changes (±SE) in muscle volume (cm3) in response to therapy with testosterone and nandrolone decanoate (ND) in tail-suspended rats as measured by MRI in comparison with no treatment (ground control); n = 10 each group. * P < 0.05, ** P < 0.01.

There were no statistical differences in the muscle volume or BMD when the ground-control rats were compared with either testosterone-treated ground controls, or tail-suspended testosterone- or ND-treated rats (Figs. 3 and 4). MRI images of the femur showed that, in comparison with the ground controls (1.17 ± 0.03 density units), placebo-treated tail-suspended rats had a significantly lower BMD in the femur (1.04 ± 0.04 density units; P < 0.05; Fig. 4). On the other hand, tail-suspended rats treated with testosterone had a femur BMD of 1.15 ± 0.04 density units (85% improvement), and the group treated with ND had a BMD of 1.13 ± 0.07 density units (a 76% improvement; P < 0.05; Fig. 4).


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  		Fig. 4.   Effects (±SE) of testosterone and ND treatment on bone mass (density units) in tail-suspended rats in comparison with ground controls as measured by MRI (n = 10 each group). * P < 0.5.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Tail suspension (i.e., simulated weightlessness) significantly decreases both muscle volume and BMD in rats as determined by MRI. In this model, testosterone-replacement and ND therapy both were able to significantly decrease the expected muscle volume and bone mass loss. Muscle volumes and bone masses of these two treated groups of rats were not statistically different from those of the ground controls. Although similar-age rats were used in both experiments in the present study, the observed difference in absolute values (muscle volume and BMD) were due to the species differences.

A negative calcium phosphate balance and decreased BMD in the peripheral skeleton, such as in calcaneum and radius bones, has been reported in rats exposed to microgravity and simulated weightlessness conditions (14, 18, 49). However, because these studies examined the peripheral skeleton, they may not reflect changes in the weight-bearing bones, particularly the spine and the hip. Mechanical loading and muscle forces play important roles in the development and maintenance of skeletal tissues (14, 19, 49). Subnormal mechanical stresses as a result of bed rest, immobilization, or spaceflights can lead to disuse osteoporosis, whereas supranormal loads on extremities result in increased bone mass (1, 8-13, 26, 32, 33, 38, 39, 43, 50).

The testes are the major source of testosterone, which serves both growth and maintenance functions for the musculoskeletal system (4, 7, 23). For example, castration in rats leads to skeletal muscle atrophy in the hormone-sensitive levator ani (44) and in other striated muscles (23), whereas supraphysiological doses of testosterone increase muscle mass and strength (7). A significant reduction in serum testosterone levels was previously reported in 12-day tail-suspended rats (45, 47, 48) and in rats flown in the 14-day Cosmos 2014 mission (30). Tail suspension, disuse of limbs, and exposure to microgravity significantly decrease bone formation and can consequently decrease BMD in rats (14, 19, 29, 34, 49). Testosterone and anabolic steroids have positive effects on osteoblasts cells in bone formation (21). The mechanism of action of androgen on bone cells involves induction of transforming growth factor-beta and may also involve sensitizing bone cells to fibroblast growth factor and insulin-like growth factor II (22). Indeed, the increase in skeletal mass in androgen-treated patients has been directly attributed to the effect of androgen on bone formation. Because testosterone is known to influence bone formation, one could postulate that a marked reduction in testosterone may be responsible, at least in part, for the decreased bone formation and consequent reduction in bone mass in tail-suspended rats, as well as humans exposed to microgravity, and its replacement should alleviate this.

Testicular testosterone levels in the rat are consistently shown to decrease in rats flown into space, as well as in a simulated space environment (16, 30). However, the data on the changes of serum testosterone levels are contradictory, involving decreases in testicular weight and testosterone levels and increases in serum luteinizing hormone and follicle-stimulating hormone in 7-day tail-suspended rats (16, 48), as well as decreases in thyroxin and testosterone secretion with no changes in serum corticosterone, growth hormone, or prolactin (30). Other studies have reported a decrease in the testicular testosterone levels but a lack of negative effect on spermatogenesis (2, 12). These authors have also pointed out that testicular abnormalities (including decreases in testicular weights and plasma volumes) are not uncommon among normal rats, and their influence on tissue and circulatory hormonal levels should be considered as well. The data interpretation is also confounded by the age of the animals used: flight animals are generally postpubertal, whereas most ground-based studies have used immature rats for suspension studies. Therefore, the data obtained with young growing rats (i.e., for serum hormones and bone histomorphometry) may not be relevant to adult humans, particularly astronauts. Levels of testosterone used in the present study were not sufficiently high to induce muscle volume in the ground-control rats, whereas in the tail-suspended rats, the same dose of testosterone maintained their muscle volume.

Using bed-rest models, researchers have shown an ~0.9% decrease in BMD per month in lumbar spines of humans (25). However, as in the case of tail-suspended rats, astronauts also show marked regional variations of loss of BMD, together with a negative calcium balance of ~300 mg/day during flights (25). MRI at 0.5 T previously has been used for quantitation of lower-limb muscle masses after bed rest in human volunteers (26). In these studies, a loss of 8.5-12.5% of the muscle volume as measured by MRI scanning over a 1-mo bed-rest period (6) was reported. The authors suggested that the volunteers exposed to daily low-negative body pressure (a head-tilt-lying position as a countermeasure to cardiovascular deconditioning) produced no changes in muscle mass, but other studies have failed to confirm this.

Some molecular and cellular events involved in weight-bearing-related musculoskeletal changes are under the influence of neural and endocrine growth factors, cytokines, and nitric oxide. Changes in serum growth hormone and fluid shifts and disrupted fluid balances may also contribute to the observed musculoskeletal aberrations in tail suspension and in microgravity (17). Several potential therapeutic agents and exercise regimens have been tried to prevent musculoskeletal losses associated with weightlessness with variable results (15). Tsika et al. (40), using a hindlimb-suspension model, showed a loss of muscle mass in fast-twitch plantaris and slow-twitch soleus muscles but not in soleus myofibril content in female rats treated with ND (40).

MRI is a very sensitive technique that can be used for measuring changes in muscle volume in this animal model (~2% loss of muscle volume/day). In this study, we have not investigated the type of muscle fibers that were changed after tail suspension and in response to pharmacological therapy, but this has been addressed by others (40). Here, we demonstrated that testosterone-replacement therapy or treatment with the anabolic steroid ND significantly decreased the expected muscle volume and BMD decrement in these tail-suspended rats. We conclude that in the tail-suspended rats, the marked reductions of serum testosterone levels may contribute to the observed significant reductions in muscle and bone masses, and replacement of this deficient hormone minimizes the observed musculoskeletal mass losses.


    ACKNOWLEDGEMENTS

This work was supported by the funds provided by the University of Texas Medical Branch at Galveston. S. M. Wimalawansa was a high school summer student.


    FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: S. J. Wimalawansa, Dept. of Internal Medicine, Univ. of Texas Medical Branch, 8.104, Medical Research Bldg., Galveston, TX 77555-1065 (E-mail: swimalaw{at}utmb.edu).

Received 19 June 1998; accepted in final form 10 February 1999.


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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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