Multi-scale Modeling of Skeletal Muscle Metabolic Adaptations to Unloading

1. Multi-scale Modeling of Skeletal Muscle Metabolic Adaptations to Unloading PI: Marco E. Cabrera Co-PI’s: Ranjan K. Dash Res. Assoc.: Marco Camesasca Fatima F. Silva Ilya Bederman Michelle A. Puchowicz Nicola Lai Stephen Previs Students: Russell Valentine Leigh Praskac Jeffrey Shuster IMAG Consortium Meeting Bethesda MA – April 11,12 2007 Grant #: NNJ06HD81G

2. Introduction • Lack of a mechanical stimulus on “weight-bearing” muscles of astronauts during prolonged space travel leads to alterations in skeletal muscle structure, metabolism, and function. • Alterations span from • Cellular (expression MHC isoforms, I-IIa) • Skeletal Muscle Fibers (CSA, protein content) • Muscle (strength, endurance, insulin resistance) • Organism (work capacity) Cabrera, Marco E.Time Course of Metabolic Adaptations during Loading and Unloading

3. Biomedical Significance • The chain of events linking alterations at cellular, tissue, and organism level are not fully understood. • Integrate multi-scale events represents • Challenge • Opportunity for computational physiology Cabrera, Marco E.Time Course of Metabolic Adaptations during Loading and Unloading

4. Specific Aims and Long-term Goal • Develop multi-scale model of skeletal muscle metabolism • Cellular biochemical processes to muscle fibers • Muscle fibers (I, IIa, IIb, IIX) to whole muscle • Skeletal muscle + other organs metabolism to whole body function • Predict integrated response of • muscle fibers • skeletal muscle • whole body at rest and during exercise, after periods of space travel. • Long-term Goal: Develop an aspect of the “Metabolome” component of the “Digital Astronaut” Cabrera, Marco E.Time Course of Metabolic Adaptations during Loading and Unloading

5. Systems Identification + Modeling • Input: mechanical stress (chronic); • Reduced: Space travel • Increased: Exercise training • System: Fibers – Whole Muscle – Whole Body • Outputs (fibers - muscle - whole body): • Glycogen breakdown (muscle – liver) • Glucose and lactate metabolism and exchange • Fuel distribution and oxidation patterns

6. Organism Organ/Tissue CO2 LAC GLU GLY O2 Cell H2O H+ G6P ACoA PYR Inputs or Perturbations Multi-scale System

7. Acute Response to Chronic Intervention Outputs Input Computer Model 150 watts System of non-linear algebraic and differential equations 0

8. Responses to Ischemia-Reperfusion G6P GLU LAC PYR

9. Responses to Ischemia-Reperfusion Cr PCr ATP Pi ADP AMP

10. Model Sharing – Integrating O2 Transport and Cellular Metabolism Lai et al. Eur J. Appl. Physiol. 2006; Vicini & Kushmerick. Am J. Physiol., 2000

11. Model Equations Lai et al. Eur J. Appl. Physiol. 2006; Vicini & Kushmerick. Am J. Physiol., 2000

12. Validation and Prediction

13. O2 Consumption and PCr Dynamics

14. Experimental Results from HSU Model Intermediary metabolism changes: Fiber atrophy has been attributed largely to a significant decrease in myofibrillar protein synthesis (69%). There is an overall fuel shift from fatty acids to glucose oxidation.

15. Modeling of Glycolytic Pathway Original SBML model implemented for integration with other pathway models via MATLAB and Fortran

16. Conclusions and Future Work • Dynamic responses of skeletal muscle and whole body can be successfully predicted from validated physiologically-based models. • Simulations predict integrated responses to acute and or chronic stimuli at various levels (cellular, tissue/organ, organism) of complexity via development and integration of “minimal” working models. • Integration of models developed differently (eg, Fortran and Matlab, SBML, libraries of algorithms) can be speeded up via common agreement of standards for data, formats and languages.