|
Principal Investigator:
|
Martin J. Kushmerick, M.D., Ph.D.
|
|
Organization:
|
University of Washington
|
|
Project Ended:
|
2004
|
Dr. Martin J. Kushmerick is producing a mechanistic model of muscle metabolism, focusing on energy supply and demand. The limb functional model will allow analysis of altered physiological responses to the space environment and research for countermeasures against space's deleterious effects.
|
Principal Investigator:
|
Martin J. Kushmerick, M.D., Ph.D.
|
|
Organization:
|
University of Washington
|
|
Project Ended:
|
2004
|
Background Human muscle performance depends on a number of factors beyond the mechanisms in neural activation and control. In fact, the experienced and trained nervous system depends on stable biomechanical properties of the muscle for skilled and reliable limb performance. The biomechanical properties depend on the size of the muscle (muscle quantity) and the phenotype of the muscle cells (muscle quality). Most of the other projects in the muscle team are concerned with the regulation of muscle mass (risk of wasting and atrophy).
This project uniquely analyzes by experiment and modeling the interplay between biomechanical properties and energy metabolism. That this is important is obvious from the facts and extensive literature on the sustainability of muscle performance and ease of fatigue. Decreased performance and fatigue is determined by an integration of muscle properties, mass of muscle and biomechanical demand. The first part of this project analyzes and quantifies the internal structures of human limb muscle, with the goal of translating external torque and length changes produced across a limb by a given muscle into the actual forces and lengths of the muscle cells experience when organized as fascicles. This work enables a cellular and mechanistic analysis well beyond what is currently done and described in the literature for human muscle.
Biomechanical power output must be matched quantitatively by biomechanical power input within the cells for sustained activity beyond a few tens of seconds. The second arm of this project applies quantitative measures of the components of energy balance (ATPases, glycolysis and oxidative phosphorylation) to measure the energetic properties of selected muscles and how these vary among individuals. These measurements are then analyzed in the third arm of this project by a quantitative model to obtain metabolic fluxes and in combination with mechanical data to obtain quantitative analyses of economy, efficiency or doing work and related parameters.
Goals
The overall goal of this project is to build up a series of measurements and models of:
- Intracellular energy and metabolic fluxes (ATP supply and demand);
- Mechanics during exercise (ATP demand); and
- Blood flow (ATP supply).
The goal will make possible an integration of the mechanisms involved and a validation of models describing these processes.
Aim One: Measure the economy and efficiency of human muscle contraction and sustainable power output.
Hypotheses tested:
- The balance between ATP supply and ATP demands account quantitatively for the difference in sustained performance (duty cycle) in various muscles and individuals.
- Working contractions add a substantially larger, myofibrillar cost above isometric twitches in which only ion transport activation costs dominate.
- Muscles differ in economy and efficiency: mechanically slower muscles have higher economy and thermodynamic efficiency for converting ATP to external work than fast muscles, but lower power.
Aim Two: Integrate the component mechanisms of energy supply and demand into models to make predictions of energy costs and balance in new experimental conditions. Hypotheses tested:
- Simple models of the components of energy balance as developed in aim one are necessary and sufficient to account for the major energetic properties of human muscle.
- The models establish a cellular basis for defining isometric economy and working efficiency.
- Variations in properties among muscles and individuals define the normal distribution of properties so this distribution can be used to define probabilistic responses of the system.
- When new mechanistic components at the molecular and cellular level are added, they can be tested for their effects on the system operation.
Relevance to Risk Reduction and Countermeasure Development Even in the presence of significant atrophy muscle may be capable of sufficient and sustainable power output provided the muscle is operating over an appropriate portion of the force-velocity and power-velocity curve and provided that there is sufficient steady state and dynamic metabolic power. While not minimizing the importance of adequate muscle mass and the deleterious effects of muscle atrophy, we focus on the equal or more important aspect of the muscle functional properties in intact humans by entirely non-invasive methods, some of which can be conducted in the International Space Station and on long-duration expeditions.
Current risk assessment is based entirely on evaluating the consequences of decreased muscle mass. The information provided by this project enables an evaluation of the consequences (both positive and negative) of altered muscle performance. The modeling enables a forward analysis of altered exercise strategies to accommodate possibly the same motor tasks. It also enables a prediction of the biomechanical responses to the muscle phenotype that would be produced by countermeasures developed by molecular and pharmaceutical procedures being investigated in other projects of the team and by exercise strategies being developed by other teams and by JSC and other NASA professionals. It is likely that the bioenergetic/biomechanical analyses would be useful in design of space suits because of the inevitable addition of mass, friction and viscosity of the suit to the overall limb function.
Print