Wouldn't it be nice to enjoy the benefits of exercise without the effort? For example, endurance physical training results in elevated muscle mitochondrial content for increased aerobic respiration and the transition of fast-twitch fibers into slower oxidative fibers. One step towards the goal of gain without pain is the elucidation of the signaling cascades that increase both metabolic and contractile capacities in muscle. Recently, it has been appreciated that one important signaling cascade during exercise involved AMP-activated protein kinase (AMPK). Indeed, the activation of AMPK can mediate some of the metabolic effects associated with exercise. However, the role of this pathway in modifying muscle contractile properties remains unclear. The paper by Charles T. Putman and collaborators examines this question and further investigates the effects of activating the AMPK pathway on glycolytic and oxidative metabolic profiles.

In order to test these hypotheses, the authors injected rats for a month with a compound, AICAR, that is known to activate AMPK. The team looked at the activity of several mitochondrial enzymes as markers of mitochondrial biogenesis, the expression of uncoupling protein-3 (UCP3), a mitochondrial protein that is associated with the regulation of burning fat and, finally, the proportion of oxidative fibers in muscle.

The first set of results in fast-twitch muscle revealed that the activity of mitochondrial enzymes was elevated in the groups of rats treated with AICAR. This result suggests that AMPK plays a role in mitochondrial biogenesis due to exercise.

Also, the increased mitochondrial biogenesis led to an increase in UCP3 in the treated rats. However, the increase in UCP3 protein level was higher than for other mitochondrial proteins, which suggests that UCP3 might be specifically targeted in mitochondria by the AMPK signaling pathway. The team suspects that as UCP3 expression has been associated with the metabolism of lipids, the preferential upregulation of this protein could be related to the increased oxidation of fatty acids that occurs during exercise.

For the second part of their study, the authors examined the expression of various myosin heavy chain isoforms, which are markers of the different fiber types in fast-twitch muscle. The proportion of oxidative fibers was not increased in AICAR-treated animals. Therefore, activation of AMPK cannot mimic the contractile adaptations that occur in muscle during endurance training.

Overall, this study shows that activation of the AMPK signaling cascade leads to some of the beneficial metabolic effects of exercise, without affecting muscle contractile properties. This type of pioneering study is fundamental to our understanding of how exercise affects organismal physiology. Finally, the search for evolutionary conserved signaling pathways in other organisms should be of great interest for comparative physiologists in the years to come.