AMPK and PPARdelta agonists are exercise mimetics.
The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.
Narkar
Vihang A
VA
Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.
Downes
Michael
M
Yu
Ruth T
RT
Embler
Emi
E
Wang
Yong-Xu
YX
Banayo
Ester
E
Mihaylova
Maria M
MM
Nelson
Michael C
MC
Zou
Yuhua
Y
Juguilon
Henry
H
Kang
Heonjoong
H
Shaw
Reuben J
RJ
Evans
Ronald M
RM
D055372:AMP-Activated Protein Kinases; D000284:Administration, Oral; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D032701:Biomimetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists*; D010805:Physical Conditioning, Animal; D010807:Physical Endurance / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
C425931:GW 501516; D009097:Multienzyme Complexes; D047494:PPAR delta; D012265:Ribonucleotides; D013844:Thiazoles; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide