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Governor recalled! Now what?

The hypothesis that AMP-activated protein kinase (AMPK) acts as the ‘metabolic governor’ has deservedly received considerable attention (Winder, 2001). Studies defining the signalling pathway are elegant, the level of effort almost Olympian in nature, and the implications mighty, in terms of both the science and the potential for clinical application. However, while new and exciting, the notion that a single pathway acts as a metabolic governor in working mammalian muscle overlooks a lot of what is known about metabolic regulation. Now, with the results of McConell et al. (2005) in this issue of The Journal of Physiology, it is time to reassess the relevance of the AMPK signalling pathway for the regulation of metabolism in working human muscle. 
 
The notion that AMPK or any other component of the signalling pathway acts as a metabolic governor begs for consideration of a definition of ‘metabolism’. Typically, metabolism is described as ‘the sum of all processes in a living organism’, and because these processes involve heat production, ‘metabolic rate’ is commonly defined as ‘the rate of heat production’ (Brooks et al. 2004). Proponents of the hypothesis of AMPK as a metabolic governor overlooked basic definitions of ‘metabolism’ and ‘metabolic rate’ and neither proposed nor provided data to show how changes in AMPK could affect ATP turnover or any other component of energy flux. To the contrary, changes in muscle AMPK level or signalling are likely to be the consequence of, rather than cause of, changes in muscle metabolic rate. Hence, in terms of applicability to the energetics of muscle contraction or any other metabolic consequence of physical exercise, the hypothesis lacked a guard against tests such as those imposed by McConell and colleagues, who uncoupled changes in metabolic rate and energy substrate partitioning from changes in AMPK signalling in muscles of men studied before and after short-term exercise training. 
 
While the AMPK hypothesis lacked a necessary component of metabolic regulation, the hypothesis did contain a component to explain energy substrate partitioning during exercise. However, by predicting that AMPK signalling could simultaneously increase working muscle glucose disposal and lipid oxidation, proponents of the hypothesis failed to appreciate classic results of indirect calorimetry on body respiratory exchange ratio (RER) or more recent results on muscle respiratory quotient (RQ) or blood glucose and fatty acid flux rates during exercise (Brooks et al. 2004). Whether from perspectives of the Randle Cycle (Randle, 1995) or Crossover Concept (Brooks & Mercier, 1994), up-regulation of the use of one energy source (e.g. glucose) should down-regulate use of other sources (e.g. lipid). The proposition that AMPK could signal increments in both glucose and lipid metabolism in working muscle was untenable as it is contrary to experience and predictions of models of metabolic regulation. And, in terms of the AMPK hypothesis itself, alarms should have gone off when it was observed that malonyl-CoA levels did not change in working human muscle and remained at a level well above the IC50 (Brooks et al. 2004). 
 
Factors that regulate muscle glycolytic and oxidative energy fluxes are powerful, well known and independent of AMPK signalling (Kushmerick & Conley, 2002). Hence, it is not surprising that the purported, but subtle, effects of AMPK signalling are overridden during contraction. But, when exercise stops RER and RQ decline, and relative lipid oxidation increases whereas carbohydrate oxidation decreases (Brooks et al. 2004). Can it then be that the impact of AMPK signalling emerges after exercise? As untenable as the AMPK signalling hypothesis is for muscle exercise, it would be a pity to now suddenly abandon it based on the study of McConnell et al. In retrospect, their efforts were necessary, but results were predictable based on results of many previous investigations. In hindsight, because consequences of AMPK signalling are easily overridden during muscle contraction when energy flux rate can increase one or two orders of magnitude, invocation of the pathway as a means to regulate metabolic rate and energy substrate partitioning during physical activity may have been misguided. It is likely that the real importance of AMPK signalling, or its absence, may emerge in other, near basal conditions such as recovery from physical activity, space flight, postprandial rest in healthy individuals or those suffering from obesity, type 2 diabetes, or other metabolic diseases where small, but persistent effects on energy substrate partitioning may have major long-term consequences. 
 
And finally, the paper of McConnell and colleagues reminds us that homeostatic regulation of high flux systems typically requires redundant controls. Such systems are seldom regulated by a single factor. Perhaps the influence of AMPK signalling on muscle metabolism during exercise is analogous to the role of hydrogen ion in the regulation of pulmonary minute ventilation and muscle blood flow. By its nature, general understanding in well-developed sciences such as physiology possesses a degree of inertia. Ultimately, science advances because outstanding hypotheses are articulated (e.g. Winder, 2001) and aggressively tested. McConnell and colleagues have tested aspects of the ‘metabolic governor’ hypothesis. Now, the actual role and conditions under which changes in AMPK affect the regulation of muscle metabolism need to be determined.