Marathon Mice: What it means for the future of healthcare

1. Marathon Mice: What it means for the future of healthcare 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. -PeroxisomeProliferator 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 Peroxisomeproliferator-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 • GW1516 investigational 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. PLoSBiol 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. <http://www.salk.edu/news/pressrelease_details.php?press_id=306>. • "Marathon Mouse." The Molecular Biology of Paradise. Web. 02 Nov. 2010. <http://www.paradise-engineering.com/somatic/index.html>.