Overview

The Multisystem Effect of Exercise Training/Nutritional Support During Prolonged Bed-Rest Deconditioning: An Integrative Approach to Countermeasure Development for the Heart, Lungs, Muscles and Bones

Principal Investigator:
Benjamin D. Levine, M.D.

Organization:
The University of Texas Southwestern Medical Center at Dallas

Sustained exposure to microgravity leads to problems in the cardiovascular, muscular and skeletal systems. The heart may shrink and atrophy, leading to fainting and low blood pressure when trying to stand. Atrophy of skeletal muscle and loss of calcium from bone can diminish strength, work capacity, and lead to injury. Appropriately delivered exercise training may be effective at preventing these problems, but it is not known what kind of exercise is best for all these systems, nor is it known how each system interacts with the others in an individual astronaut who has only a limited amount of time available to perform exercise in space. Based on data from highly trained athletes and previous bed-rest simulations, Dr. Benjamin D. Levine is researching whether the combination of rowing plus strength training, when combined with a specially designed nutritional supplement (potassium-magnesium-citrate) could serve as a single, integrated approach to prevent bone demineralization, cardiovascular deconditioning and muscle atrophy during prolonged bed rest, with the ultimate goal of applying it in astronauts in future missions.

NASA Taskbook Entry

Technical Summary

Original Aims
Sustained exposure to microgravity leads to adaptive changes in the cardiovascular and musculoskeletal systems that result in substantial morbidity. For example, cardiovascular deconditioning may lead to orthostatic hypotension and syncope. Atrophy of skeletal muscle will diminish work capacity and may lead to muscle injury. Bone demineralization increases the risk of kidney stone formation and may reduce bone strength, increasing the risk of fracture. Bone resorption may be particularly severe after long-duration spaceflight with uncertain recovery.

Despite in-depth study, the optimal countermeasure for each system has not been defined. More importantly, previous work has focused predominantly on one organ system at a time, ignoring the interaction among systems and preventing the development of a specific countermeasure for an individual astronaut that might be effective for the heart, muscles and bones. The global objective of this project is to test an integrated countermeasure that will be effective against cardiovascular deconditioning, skeletal muscle atrophy and bone demineralization, and ultimately can be applied practically abroad the International Space Station or a mission to Mars.

Hypothesis

An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.
This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate (KMgCit) supplementation, will attenuate the increased risk for kidney stone formation and diminish bed-rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.
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.

Specific Aims

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 left ventricular pressure/volume curves), in conjunction with innovative, noninvasive 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.
To assess the effect of exercise training combined with supplementation with KMgCit in preventing microgravity-induced increases in bone resorption, urinary calcium excretion and risk of kidney stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus noninvasive evaluation of bone structure and function (bone quality by ultrasound).
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, morphometry and capillary density).

Key Findings

Subjects who exercised had preserved cardiac structure and function, cardiac muscle mass as well as the mass/volume ratio were preserved, and both Frank-Starling and pressure-volume curves were superimposable.
In contrast, those who were sedentary during bed rest had the expected leftward shift of their pressure/volume curves, similar to that observed after short-duration bed rest. This shift was observed even if transmural pressure was used as the independent variable to the pressure/volume curves.
Exercising subjects had no loss of peak work capacity or maximal oxygen consumption (VO₂ max), both of which decreased by approximately 25 percent in the sedentary subjects.
Those exercising subjects who received the oral volume load were protected against orthostatic intolerance with maximal lower body negative pressure tolerance virtually identical to baseline levels despite five weeks of head-down tilt bed rest.
Muscle strength was preserved, as was histochemistry, mitochndrial function and capillarity in the exercisers, while all decreased in the sedentary subjects.
Urinary calcium loss was attenuated, especially in those volunteers given KMgCit, though exercise did not appear to have a prominent effect on markers of bone demineralization.
Dual energy x-ray absorptiometry scanning at the hip suggested that exercisers were protected from a small, but measurable, loss of bone mass during five weeks of bed rest.

Earth Applications

The information obtained from these experiments will be relevant for patients with prolonged confinement to bed rest or chronic reduction in physical activity, as well as for patients with disease processes that alter cardiac stiffness such as obesity, hypertension, heart failure or ischemic heart disease, plus normal aging and osteoporosis. Indeed, we are already using this strategy to treat patients with chronic orthostatic intolerance and Postural Orthostatic Tachycardia Syndrome with outstanding results. Rowing and strength training have been incorporated into my standard clinical algorithm for management of these patients, all of whom have very small hearts. This work has led to the elaboration of a new name for this important clinical syndrome: "The Grinch Syndrome" (because their hearts are "two sizes too small").

This project's funding ended in 2010