This project is aimed at characterizing the molecular mechanisms of muscle fatigue in order to develop novel therapies to treat the debilitating symptoms of fatigue in individuals with chronic heart failure. Our current understanding of the muscle fatigue is limited by our inability to directly observe this process at the molecular level. This project will overcome this barrier by harnessing the latest technological advances in the field of biophysics to directly visualize the process of muscle fatigue at the level of a single molecule. It is a highly collaborative project in which world renowned investigators from the Medical Colleges of Pennsylvania State University and The Ohio State University will help Dr. Debold characterize the causes of fatigue at the most minute molecular levels. This knowledge is crucial for the development of new therapies because it is at this level where the most promising new pharmaceutical therapies will act to attenuate the symptoms of fatigue. In fact, the final aim of this project will take the first steps toward translating this knowledge by testing the ability of several new pharmaceutical compounds to attenuate the depressive effects of fatigue at the molecular level, in collaboration with the private sector. The knowledge gained from this project will transform our understanding of muscular fatigue and could lead to important therapeutic breakthroughs that will greatly improve the physical function and quality of life for the 5.7 million Americans suffering from chronic heart failure. It was one of only 6 of the 116 proposals submitted to be funded, thus Dr. Debold and his team feel extremely fortunate to have had their work deemed so important to the mission of the American Heart Association. This represents the third grant that Dr. Debold has received from the AHA, therefore they have now provided a total of $534,000 to support his research program.