1. Joellen Little-Kemper November 9, 2010

2. Introduction Imagine that the activation of a single gene could result in increased: *obesity resistance *insulin sensitivity *muscle fiber specification *physical endurance Howard Hughes Medical Institute and Salk Institute found just that. -Peroxisome Proliferator Activated Receptor (PPAR-delta)

3. Skeletal muscle fibers have 2 classifications: Type I-slow/oxidative Type II-fast/glycolytic Adult skeletal muscle plasticity Can be mediated by a calcium signaling pathway that involves calcineurin, calmodulin-dependent kinase, and Peroxisome proliferator-activated receptor-gamma coactivator 1a (PGC-1a)

4. PPAR-delta PPAR-delta is a major transcriptional regulator of fat burning in adipose tissue Activation of the PPAR-delta was assessed for its control of muscle fiber plasticity and mitochondrial biogenesis The PPAR-delta transgene VP16 activation domain Human a-skeletal promoter

7. PPAR-delta and obesity resistance TG mice and their WT littermates were fed a high-fat diet for 97 days. All the TG and WT had the roughly the same initial body weights By day 47, the TG gained 50% less than the WT By day 97, the TG gained only 1/3 of the weight gained by the WT By the end: WT-obese TG- normal body mass/fat composition; also displayed higher oxygen consumption on the high fat diet than the WT

9. Enhancement of Physical Performance through PPAR-delta Comparison of exercise performance between untrained, body-weight- matched TG and WT littermates. Mice were run on oxygen infused, enclosed treadmills until exhaustion The TG mice were found to: Time: run 67% longer than the WT Distance: run 92% farther than the WT No significant differences in muscle mass and daily activity of the 2 groups (TG and WT) were observed Therefore, the increased endurance had to do with the physiological manifestation of muscle fiber transformation.

10. Video Demonstration

12. Conclusions: PPAR-delta and its ligands are a key switch in the regulation of: Muscle fiber specification Obesity resistance Insulin sensitivity Physical endurance

13. What these conclusions mean Could we eventually have exercise in a pill? Therapeutic potential for the treatment of certain muscle diseases (such as wasting and fragility), obesity, and metabolic disorders GW1516investigational drug Benefits of lowering fatty acid and blood glucose levels, but no effect on exercise performance in sedentary animals When combined with a regulated exercise regimen (50 minutes of daily exercise on the treadmill), it improved endurance by 77% over exercise alone.

14. References Wang Y-X, Zhang C-L, Yu RT, Cho HK, Nelson MC, et al. (2004) Regulation of Muscle Fiber Type and Running Endurance by PPARδ. PLoS Biol 2(10): e294. doi:10.1371/journal.pbio.0020294 "Salk Institute - Press Releases - Exercise in a Pill." Salk Institute | Where Cures Begin. Web. 02 Nov. 2010.. "Marathon Mouse." The Molecular Biology of Paradise. Web. 02 Nov. 2010..