Exercising women throw a wrench in the gears of the AMPK–lipid oxidation link

Several studies, including one in this issue of The Journal of Physiology (Roepstorff et al. 2006), have found that women oxidize more lipid than men during endurance exercise (Friedlander et al. 1999; Carter et al. 2001). The carefully controlled study reported in this issue (Roepstorff et al. 2006) evaluated AMPK signalling as a mechanism for a sex difference in metabolism by evaluating the potential role of AMPK in the regulation of skeletal muscle fat oxidation during exercise. It has been suggested that AMPK is a skeletal muscle energy sensor responding to elevated free AMP content during muscle contraction, which, in turn, inactivates acetyl CoA carboxylase, decreases malonyl CoA and removes its inhibitory effect on CPT1 activity (for review see Hardie & Sakamoto, 2006). Roepstorff et al. had moderately trained males and females complete 90 min of cycling at 60% and found that skeletal muscle AMPK Thr172 and α2AMPK activity increased significantly with a concomitant increase in free AMP, the AMP/ATP ratio and free creatine in men, but not women (Roepstorff et al. 2006). These data suggested the higher lipid oxidation seen in women during submaximal endurance exercise was associated with lower ‘cellular energy stress’, but not with AMPK status (Roepstorff et al. 2006). Consequently, the results of the current study suggest that either the AMPK–fat oxidation relationship is more complicated than originally proposed, or that the regulation of fat oxidation is independent of AMPK in women. They also confirmed earlier reports of a higher proportion of type 1 muscle fibres in women (Carter et al. 2001), and added novel data showing a correspondingly higher capillarization (∼23%). These latter findings suggest that fibre type and capillarization can partially explain the sex difference in metabolism; however, there must be other factors at work given that acute 17-β-oestradiol administration can influence exercise substrate selection within days (Devries et al. 2005), which is far too rapid for capillarization or fibre type transformation to occur. In the future, it will be of great interest to determine the role of 17-β-oestradiol on AMPK activity and its ultimate effect on capillarization and fibre type. Initial insight into this could be gleaned from the AMPK mRNA and protein abundance and phosphorylation status in response to acute 17-β-oestradiol administration; however, fibre type and capillarization influences will likely require longer term animal studies. As is the case with every study done well, more questions and research ideas are generated, particularly with respect to the AMPK–fat oxidation relationship in human skeletal muscle. Researchers in every aspect of exercise physiology will be further reminded of the need to control for potential sex differences and metabolism in all aspects of research design.

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