Multi-scale Model of Whole Body to Predict Integrated Metabolic Response to Space Travel
- Paper number
IAC-05-A1.3.02
- Author
Dr. Marco Cabrera, Case Western Reserve University, United States
- Coauthor
Mr. Russell Valentine, Case Western Reserve University, United States
- Coauthor
Dr. Ranjan Dash, Case Western Reserve University, United States
- Year
2005
- Abstract
Background and Significance: The alterations in skeletal muscle structure and function induced by prolonged space travel result from chronic lack of a mechanical stimulus of sufficient intensity and a series of biochemical and metabolic interactions spanning from the cellular to the whole-organism level. Reduced activation of weight-bearing muscles alters gene expression of myosin heavy chain isoforms and leads to muscle atrophy, reduced capacity to process fatty acids, and reduced muscle endurance. The few studies comparing skeletal muscle structure and function before and after unloading have provided enough data to conclude that the aforementioned adaptations are time dependent and affect each biological level differently. To obtain quantitative understanding of both inter-level and intra-level interactions a hierarchical multi-level systems model is required. Objective: To develop a multi-scale systems model of human metabolism that can predict, via computer simulations, physiological responses to acute exercise after periods of space travel. Methodology: A novel top-down modeling approach has been applied to model whole-body metabolism and to bridge organism to organ-tissue level and tissue to cellular level. This minimal systems but comprehensive model of the whole body focuses on metabolism and includes: (a) brain, heart, liver, adipose tissue, and skeletal muscle as metabolic organs/tissues; (b) a cardio-respiratory controller (lungs as gas exchanger and heart as a mechanical pump) to regulate blood flow and gas exchange; (c) the pancreas and liver, to regulate glucose and fatty acid metabolism; and (d) cardiovascular system for delivering fuels, O2, and insulin/glucagon, and for removing CO2 and metabolic intermediates. The underlying methodology involves mathematical modeling of the dynamics of mass transport and chemical reaction processes of in vivo subsystems at each level of complexity included and systems identification of time-varying “adaptive” parameters. Modeling of transport phenomena across the tissue-specific membranes -which encompasses the transport of proteins, glucose, and fatty acids from the circulation into the tissue cells- constitutes an essential feature of the integration process linking the various scales. Consequently, the tissue models distinguish blood, cytosol, and mitochondrial domains as well as sub-domains within them. Passive and carrier-mediated transport of species is used between the distinctive domains, while domain-specific reaction processes are expressed as Michaelis-Menten functions of reactants and products. Results: The developed multi-scale model of energy metabolism enables testing of physiologically-feasible time profiles of the metabolic adaptations to unloading in every organ/tissue described, which would otherwise require the collection of hundreds of samples in thousands of animals. Specifically, the developed multi-scale model can be used to predict tissue metabolic characteristics (e.g., fuel efficiency, buffering capacity, muscle endurance), as well as whole body metabolism (e.g., insulin resistance, lactate acidosis, work capacity). Conclusions: A multi-scale model of whole-body metabolism is essential to integrate cellular metabolic processes to whole organism metabolism and to predict physiological responses to unloading. We envision that this computational model of human bioenergetics would become an essential component of the “Digital Astronaut”.
- Abstract document