The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An "optimized" exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific Aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound).

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: We completed all experiments on our projected N of 27 subjects last year and have used the current no-cost extension to finalize all the data analysis and write papers. The key outcomes can be summarized as follows: a) subjects who exercised had preserved cardiac structure and function - cardiac muscle mass as well as the mass/volume ratio were preserved, and both Starling and pressure-volume curves were superimposable; b) in contrast, those who were sedentary during bedrest had the expected leftward shifted of their p/v curves, similar to that observed after short duration bedrest. This shift was observed even if transmural pressure was used as the independent variable to the p/v curves; c) exercising subjects had no loss of peak work capacity or VO2max, both of which decreased by ~25% in the sedentary subjects; d) those exercising subjects who received the oral volume load were protected against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest; d) Muscle strength was preserved, as was histochemistry, mitochondrial function, and capillarity in the exercisers, while all decreased in the sedentary subjects; e) urinary calcium loss was been attenuated, especially in those volunteers given KMgCit, though exercise did not appear to have a prominent effect on markers of bone demineralization; f) DEXA scanning at the hip suggested that exercisers were protected from a small but measurable loss of bone mass during 5 weeks of bedrest.

3). Impact on objectives: None: objectives completed

4). Plan for upcoming year: The grant is completed. We will press on with getting the papers published!

The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound).

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: In the third year of the project, we accelerated the recruitment and study of our entire cohort because of exigencies of funding within our GCRC. In particular, UT Southwestern was awarded a Clinical Translational Science Award which did not fully fund our GCRC. Although many of these problems have since been solved, we were concerned that it would have been possible that the GCRC could have closed, or severely limited services for the next year. Therefore we have studied (and expended grant funds) for the majority of next years proposed subjects as well as this years. Specifically 74 subjects were screened, 23 subjects have completed all phases of the study, and 26 subjects have completed the pre-testing and bedrest component. One subject will finish with his bedrest exposure next week, and he plus a remaining 3 subjects will complete their post re-ambulation studies over the next month thus completing our proposed cohort. Data analysis will continue aggressively and we will focus on our key outcome variables to ensure that we are adequately powered for our primary analysis. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although data analysis is not yet complete, all results point in the direction of supporting our hypotheses. Subjects who exercised and received the oral volume load were protected against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

3). Impact on objectives: None.

4). Plan for upcoming year: The plan for the next year will be to complete data analysis and begin paper writing. If underpowered for key outcome variables, we may need to study another 3-6 subjects, but we do not expect this to be likely.

The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound) .

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: In the second year of the project, 19 new subjects have been screened for the study (total = 46), twelve have completed all phases of the study, a 13th subject is in the middle of bedrest, and the 14th will start next week. Nine of the completed subjects were in the exercise arm, and three subjects were in the sedentary arm. There have been no adverse events. Two subjects left the study after completing all initial evaluations -- one because she elected to join a different research study from a pharmaceutical company, and a second because of a sudden, unexpected death in the family. We already have the next subject recruited and his pre-bedrest studies are scheduled. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although we will not perform a preliminary data analysis to avoid reducing statistical power, all results point in the direction of supporting our hypotheses. Subjects who exercised and received the oral volume load have had complete protection against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

3). Impact on objectives: Based on the first two years' data and performance, we have not changed any of our hypotheses, and not altered the protocol.

4). Plan for upcoming year: The plan for the next year will be to continue a high rate of subject recruitment. We have permission to enroll 2 patients simultaneously, and therefore expect the experiment to be completed on time and within budget.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims: Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing. Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound) . Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: In the first year of the project, 27 subjects have been screened for the study, five have completed all phases of the study, and the sixth subject has just started bedrest. Three of the completed subjects were in the exercise arm, and two subjects were in the sedentary arm. There have been no adverse events, and all recruited subjects have completed all the study procedures with high quality data. We already have the next subject recruited and his pre-bedrest studies are scheduled. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although we will not perform a preliminary data analysis to avoid reducing statistical power, all results point in the direction of supporting our hypotheses. Both subjects who exercised and received the oral volume load have had complete protection against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

3). Impact on objectives: Based on the first year's data and performance, we have not changed any of our hypotheses, and not altered the protocol.

4). Plan for upcoming year: The plan for the next year will be to continue a high rate of subject recruitment. Our GCRC has just been renovated, and we hope to be able to study more subjects in parallel as one short term bedrest funded by Dr. Crandall comes to a close.

The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound).

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

[Ed. note: FY2005 record added to Task Book December 2009 when discovered it missing]