This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The effects of spaceflight on various physiological systems are clearly profound, and despite extensive research are incompletely understood. It is widely recognized, within both the space and scientific communities, that even short periods of exposure to microgravity can produce vestibular dysfunction, losses in muscle strength and function, and loss of orthostatic tolerance. Hence, there is a substantial amount of concern regarding the physiological deconditioning that might occur during longer duration spaceflights, for instance to Mars. Within this context, several countermeasures have been developed, but none appear to be completely effective. Therefore, a program priority of NASA's Biomedical Research and Countermeasures Program (NRA-03-OBPR-04) is to determine the potential usefulness of artificial gravity as a countermeasure, especially with respect to skeletal muscle atrophy and loss of muscle function. As Burton noted (15,16), the most obvious countermeasure to microgravity is a centrifuge, yet it has been the least explored. There are some obvious applications of artificial gravity as a countermeasure to microgravity. For instance, artificial gravity could be used to impose orthostatic challenges on the cardiovascular system, possibly preventing the loss of orthostatic tolerance that occurs as a result of microgravity. There are also some potential applications of artificial gravity in a microgravity environment that are not as obvious. As an example, artificial gravity/hypergravity in a microgravity environment could be used as a novel method of performing resistance training under high loading conditions. The novelty of artificial gravity/hypergravity resistance training is that each element of the body is loaded proportionally to the local gravitational field, and under hypergravity conditions muscles like those of the leg can be made to work against very high loads (e.g., + 2 body weights) without the need for external weights. For instance, performing squats (a target exercise performed by astronauts on the International Space Station) under a hypergravity load of 2 body weights would be approximately equivalent to an individual (body weight of 200 lbs) performing squats using a 200 lb weight in a normal 1 G environment. Given this background, the current proposal is a 'proof-of-principle' of a unique countermeasure technology referred to as the 'Space Cycle.' The Space Cycle is a human powered centrifuge that can be used to generate various levels of artificial gravity (53; see Figure 1, APPENDIX A). To our knowledge, the Space Cycle is the only human powered centrifuge in the United States that is currently operational. The primary objective of this proposal is to use the Space Cycle to address the following general hypothesis: Artificial gravity can be used as a unique resistance training modality that acts as an effective countermeasure to microgravity, preventing the loss of muscle mass and function. In addressing this issue, a logical sequence of experiments is proposed with the following objectives: i) determine if squats under hypergravity conditions and without external weights can produce foot forces similar to those seen when performing squat resistance training (SRT) under normal 1 G conditions; ii) determine if squats performed under hypergravity conditions produce muscle adaptations similar to those seen using a squat resistance training program under normal 1 G conditions; iii) determine if squat hypergravity resistance training (SHRT) program is an effective countermeasure to simulated microgravity. For the purposes of this grant proposal, we are focusing on SRT because squats recruit a broad spectrum of muscles in the leg and back, and are one of the classical exercises used by bodybuilders and athletes to hypertrophy muscles of the leg. Additionally, the so-called antigravity muscles of the leg are at the greatest risk for atrophy induced by microgravity. Furthermore, as noted above, squats are a target exercise performed by astronauts on the International Space Station. In achieving the objectives noted above, it will be possible to test the following hypotheses. 1. Foot force hypothesis: Previous studies show that hypertrophy of skeletal muscles occurs when they contract under high loading conditions. Perhaps the best illustration of this is the development and popularization of the repetition maximum (RM) concept that was initially pioneered by DeLorme (26). Using the Space Cycle, we hypothesize that it can be used to create hypergravity-loading conditions that result in foot forces similar to those seen when performing a 10 RM set of squats in a normal 1 G environment. 2. Hypergravity resistance training (SHRT) hypothesis: By definition, SHRT will always refer to resistance training that employs hypergravity as the loading modality rather than external weights. This hypothesis states that SHRT on the Space Cycle under conditions that produce foot forces similar to those seen when performing SRT in 1 G will result in muscle hypertrophy (just as is seen under normal 1 G conditions). 3. Countermeasure hypothesis: This hypothesis states that SHRT can be used as an effective countermeasure to microgravity, preventing the loss of muscle mass and function normally associated with exposure to microgravity. Development of the Space Cycle. As described in APPENDIX A, we have developed two versions of the Space Cycle. The newest version of the Space Cycle has a radius of 6 feet and is compatible with the dimensions of the International Space Station. The Space Cycle has an aluminum frame that houses a moving drive system and restraints for riders. The frame can be configured so that the legs and/or upper body musculature are required to produce power. Additionally, the centrifuge arms can be easily removed and modified according to the type of activity desired. The physiological instrumentation of the Space Cycle includes: i) instrumented foot pedals that can be used to measure torque, work, and power; and ii) monitors for blood pressure, heart rate, and oxygen consumption (using a ViaSys VmaxST telemetry unit). Work and power are controlled using a caliper brake system and are monitored by telemetry. For the purposes of the current grant proposal, the passive centrifuge arm will be modified such that subjects can perform squats under hypergravity conditions. Testing of the Space Cycle. Fourteen subjects have been tested on the Space Cycle to date. The initial set of experiments on the Space Cycle were intended to evaluate: i) the development of motion sickness; ii) blood pressure response; iii) heart rate response; iv) G-tolerance; and v) importance of duration of Space Cycle activity on various responses (e.g., motion sickness, blood pressure response). With respect to the first issue, the Space Cycle does not produce motion sickness as long as the subject does not move his/her head side-to-side or rapidly decelerate the Space Cycle. Head movement along the Gz axis is well tolerated, and, hence, SHRT should not produce motion sickness or disorientation. Importantly, it should be noted that some riders have been on the Space Cycle for durations of 2 hours at a time and on consecutive days. Therefore, we have a high degree of confidence that the proposed studies will be well tolerated by subjects. The data for blood pressure and heart rate response are reported in APPENDIX A. These data clearly demonstrate that the response of riding at 2 Gz was very similar to that of upright cycle ergometry. Six subjects have been tested up to 3 Gz (60 RPM) for a period of ~10 minutes. None of these subjects experienced motion sickness, hypotension, or fatigue. Hence, we have established that the Space Cycle can be tolerated under a number of conditions, and that the experiments proposed in this grant can be performed safely. Torque-velocity measurements of the knee extensors and flexors. The P.I. has examined the effects of training and injury on the torque-velocity relationship of the knee extensors and the plantar flexors of the ankle. With respect to training (see J. Appl. Physiol. 51(3):750-754, 1981), the P.I. examined the concept of speed-specific training. In this study, subjects trained under two isokinetic conditions (i.e., slow, or fast angular velocities). Training at the slow angular velocity produced a training effect that was speed-specific, i.e., the greatest improvement in strength occurred at the slower angular velocities. Consistent with this observation, those subjects that trained at the fast angular velocity had the greatest improvement in torque production at these velocities and the least at the slower angular velocities. Having demonstrated that isokinetic training produces speed-specific improvement in the torque-velocity relationship of the knee extensors, a study was undertaken to examine the influence of closed and open partial menisectomies on the torque-velocity relationship of the knee extensors (see Am. J. Sports Med. 11(4):189-194, 1983). This study was conducted to examine the possibility that injury/surgery might produce speed-specific impairment. The findings from this study demonstrated that both groups of patients (i.e., closed, open menisectomies) had larger strength deficits at the high angular velocities as compared to the slow angular velocities. The importance of these studies relevant to the current proposal is that it demonstrates the ability to make functional measurements of knee extensor function. Additionally, it indicates the ability of the P.I. to conduct human experimentation. The effect of Achilles tendon rupture upon the torque-velocity relationship of the plantar flexors of the ankle was studied in 31 patients (see Clin. Ortho. Rel. Res. 279:237-245, 1992). Isokinetic measurements of torque were made at angular velocities of 0 to 240 /s at 24 /s intervals. These measurements were made at joint angles corresponding to neutral and 10o plantar flexion. Two groups of patients were studied: i) open surgical repair of the Achilles tendon; and ii) closed cast treatment of the Achilles tendon rupture. Both groups exhibited a speed-specific impairment with the loss of muscle strength being greatest at slow speeds. Additionally, surgical treatment appeared to result in better functional results as determined by the torque-velocity measurements. The importance of this study relevant to the current proposal is that it demonstrates the ability of the P.I. to make functional measurements of the plantar flexors in humans. Muscle biopsies of the human vastus lateralis muscle. In this series of studies (JAMA 252:482-483, 1984; Am J. Sports Med. 14:77-82, 1986), muscle biopsies of the vastus lateralis were taken from 30 elite swimmers. Many of these athletes were swimming 18,000 m/day. All athletes returned to their normal training program the day following the muscle biopsy. Results from the study demonstrated that long distance swimmers had a higher percentage of slow Type I fibers than either middle or short distance swimmers. With respect to the current proposal, this study demonstrates that the investigative team has performed percutaneous needle biopsies of the human vastus lateralis, and that this was done in high performance athletes without incidence. Additionally, we have recently performed muscle biopsies of the vastus lateralis of subjects before and after 4 days of ULLS. Three muscle biopsy samples were obtained at each time point, and subjected to a wide array of analyses (see APPENDIX C). The types of analyses shown in APPENDIX C demonstrate that we have the capability of examining a wide range of issues at both the protein and molecular levels. Myosin heavy chain analyses of human skeletal muscle. The P.I.'s laboratory has examined the myosin heavy chain composition of the multifidus muscle (i.e., spine extensor) in approximately 50 patients. The multifidus muscle is composed of approximately 70% slow Type I, 22% fast Type IIA, and 8% fast Type IIX/IIB MHC protein isoforms. The importance of this study with respect to the current proposal is that it demonstrates the ability to separate the MHC protein isoforms of human skeletal muscle. Additionally, Dr. Adams reported (J. Appl. Physiol. 74(2):911-915, 1993) on the effects of a 19 wk resistance training program on the MyHC isoform composition of the human vastus lateralis muscle. The findings from this study indicated that resistance training reduced the relative amount of the fast Type IIX/IIB MyHC isoform and concomitantly increased the relative amount of the fast Type IIA MyHC isoform. The relevance of this study is that it demonstrates the expertise of Dr. Adams in analyzing the MyHC isoform composition of human skeletal muscle. Magnetic resonance imaging determination of muscle cross-sectional area. Dr. Adams has been involved in several studies (see J. Appl. Physiol 72(4):1493-1498, 1992; Aviat. Space Environ. Med. 65:1116-1121, 1994, Aviat. Space Environ. Med. 63:678-683, 1992) that examined the effects of simulated microgravity on the cross-sectional area of human skeletal muscles. Using this technique, Dr. Adams (see Aviat. Space Environ. Med. 65:1116-1121, 1994) reported that 16 days of unilateral lower limb suspension (see APPENDIX B) produced a 8% decrease in the cross-sectional area of quadriceps muscles. Dr. Adams participated in another study that used MR imaging and found that 6 wks of lower limb suspension produced a 12-15% reduction in the cross-sectional area of the vastus lateralis. Collectively, these findings are important in order to demonstrate the ability of Dr. Adams to use MR imaging for the determination of skeletal muscle cross-sectional area.
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