This is such an interesting review and highlights the mysteries of endurance and stamina
Baar1 & Hardie 2008 Small molecules can have big effects on endurance, Nature Chemical Biology 4, 583 – 584 (2008)
Adaptation of muscle to endurance exercise training involves the coordinated expression of genes involved in oxidative metabolism, resulting in increased endurance. A recent study shows that small-molecule activators of two pathways thought to transduce these effects can enhance the effects of training, or even substitute for it.
Skeletal muscle responds to repeated exercise by altering its contractile properties and its metabolism. Endurance training results in an increased capacity to generate energy (in the form of ATP) from aerobic pathways. An intriguing possibility is that small molecules that activate the pathways triggering these adaptations might mimic the effects of training without the accompanying sweat and effort
Muscles of transgenic mice expressing an activated form of PPAR- contain a greater proportion of type 1 fibers (characterized by a more efficient form of myosin and a higher oxidative capacity) and display increased endurance. PPAR- is a transcription factor of the nuclear receptor family; its natural activating ligand remains unknown, although one idea is that it is a fatty acid metabolite generated during muscle metabolism. However, small molecules that activate this receptor (for example, GW1516) have been developed. Narkar et al.1 now report that although prolonged treatment of mice with GW1516 induced a subset of genes involved in fatty acid oxidation, it did not increase endurance on its own. However, when the drug was combined with treadmill training, gene expression, mitochondrial mass and endurance all improved more than with training alone
AICAR is a nucleoside that is taken up into muscle and converted into the nucleotide ZMP, which mimics the effects of the natural ligand, 5′-AMP, on AMPK. The latter is produced by adenylate kinase acting on ADP generated from ATP during muscle contraction. Activated AMPK in the nucleus (an heterotrimer) then promotes expression of oxidative genes, in part by upregulating PGC-1 and switching on promoters with binding sites for PPAR- and its partner RXR. PPAR- can also be activated by GW1516, which may mimic a natural ligand produced by increased muscle metabolism. These dual mechanisms trigger expression of genes (including genes involved in fatty acid oxidation) that increase ATP production and hence endurance.
Another signaling pathway that mediates many exercise effects involves the AMP-activated protein kinase (AMPK). Increased ATP use during prolonged muscle contraction is thought to increase the concentration of 5′-AMP, its activating ligand. One target downstream of AMPK is PGC-1 , a transcriptional co-activator recruited to gene promoters by members of the nuclear receptor family, including PPAR- . PGC-1 is known to facilitate many of the adaptations to endurance exercise, including mitochondrial biogenesis and angiogenesis4. Narkar et al. tested whether the additive effect of training and GW1516 on PPAR- target genes could be mimicked using AICAR, a nucleoside that is converted to an AMPK activator inside muscle cells5. Interestingly, they found that four weeks of AICAR treatment caused modest increases in endurance on its own—that is, without training or GW1516.Previous research has shown that shorter periods of AICAR treatment in rats upregulate expression of the glucose transporter GLUT4 and mitochondrial proteins, and increase glycogen content, all of which would be expected to improve endurance. Second, transgenic expression of an activated AMPK mutant in mouse muscle results in an increase in glycogen content and endurance capacity8. Nevertheless, the new paper does provide proof of concept that small-molecule activators can increase endurance. They also report new data suggesting that AMPK is present inside the cell in a complex containing both PPAR- and PGC-1 . However, the finding that treatment with AICAR is sufficient to improve endurance on its own, whereas treatment with GW1516 is not, suggests that AMPK has additional effects not mediated by PPAR- .
The authors caution human athletes undergoing high-level endurance training (as opposed to sedentary mice maintained in a cage), that both of these pathways will already be regularly activated and the drugs may yield no additional benefit. It is also worth pointing out that the increases in endurance seen in these studies were in exercise of moderate intensity, where there is a greater reliance on fat as a fuel. These conditions may magnify any effects of GW1516, whereas in a human athletic event of an hour or less (when carbohydrates would be the primary fuel), any performance benefits of GW1516 would be minimized. The real benefit of drugs that activate PPAR- and AMPK may lie in treating people who would receive health benefits from regular exercise, but who are unable to tolerate it.

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