Joellen Little-Kemper November 9, 2010. Introduction Imagine that the activation of a single gene could result in increased: *obesity resistance *insulin.

Marathon Mice: What it means for the future of healthcare

Joellen Little-KemperNovember 9, 2010

IntroductionImagine 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)

Skeletal muscle fibers have 2 classifications:Type I-slow/oxidativeType II-fast/glycolytic

Adult skeletal muscle plasticityCan be mediated by a calcium signaling

pathway that involves calcineurin, calmodulin-dependent kinase, and Peroxisome proliferator-activated receptor-gamma coactivator 1a (PGC-1a)

PPAR-deltaPPAR-delta is a major transcriptional

regulator of fat burning in adipose tissueActivation of the PPAR-delta was assessed for

its control of muscle fiber plasticity and mitochondrial biogenesisThe PPAR-delta transgene

VP16 activation domain Human a-skeletal promoter

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 weightsBy day 47, the TG gained 50% less than the WTBy day 97, the TG gained only 1/3 of the weight

gained by the WTBy the end:

WT-obeseTG- normal body mass/fat composition; also

displayed higher oxygen consumption on the high fat diet than the WT

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 exhaustionThe 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.

Video Demonstration

Conclusions:PPAR-delta and its ligands are a key switch in

the regulation of:Muscle fiber specificationObesity resistanceInsulin sensitivityPhysical endurance

What these conclusions meanCould 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.

ReferencesWang 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. <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>.