Abstract Exercise is a powerful and pleiotropic physiological stimulus that helps prevent many chronic diseases and is used as a therapeutic for disease. While the beneficial effects of exercise are extensively acknowledged there is still very little understood about the molecular transducers of the systems-wide effects. The goal of this University of Florida Molecular Transducers of Physical Activity Preclinical Animal Study Sites application (UF PASS) is to conduct experiments in animals that will provide tissues/blood (i.e. biospecimens) to the Chemical Analysis Sites for identification of molecular transducers induced by defined models of physical activity from tissues that cannot be obtained from humans as well as to conduct mechanistic studies that can support screening of novel transducers to quickly move the field forward. In Phase 1, UF PASS proposes to collect biospecimens for the Chemical Analysis sites following endurance (run-training) or resistance exercise protocols on male and female Fischer 344xBrown Norway rats (F344-BN) at three different ages. To better capture the dynamics of the exercise/adaptation responses we propose to: 1) Collect biospecimens at 5 selected timepoints following an acute bout of exercise on nave and trained rats; 2) Collect biospecimens following short duration training (after 5 bouts) and 3) Collect biospecimens following long-term (8 weeks) training. For Phase 2, our hypothesis is that factors released from muscle (i.e. myokines) are the molecular transducers that function throughout the system to improve the well-established stress tolerance. The goal of these studies will be to employ high throughput screening technologies to test up to 1500 myokines. We will then use secondary screening techniques to test 100 candidates from which we will select up to 3 candidates for in vivo testing. The results of the experiments in Aim 3 will provide molecular evidence identifying a set of transducers, released from muscle, that are necessary for exercise induced systemic health. The goals of the UF PASS will be pursued by the following Specific Aims: Specific Aim 1: Center Coordination Phase. Specific Aim 2: Phase 1 Studies. To perform endurance and resistance exercise using male and female F344BN rats at 3-4, 16-18, and 27-29 mo. Specific Aim 3: Phase 2 Studies. The goal in Aim 3 is to test myokines as the exercise transducers for improved stress tolerance.