Resistance Exercise vs. Endurance Exercise: Different Effects on AMPK and mTOR Activities

This article [Atherton et al., 2005: (http://www.fasebj.org/cgi/content/full/19/7/786)(http://www.ncbi.nlm.nih.gov/pubmed/15716393?dopt=Abstract)] shows that the high-frequency stimulation of muscles, which supposedly mimics the effects of resistance exercise, does not predominantly activate the often-discussed AMPK-PGC-1alpha pathway but instead leads to increases in protein synthesis by activating the mTOR pathway, by first activating protein kinase B. In contrast, the authors used low-frequency stimulation of muscles to reproduce the effects of endurance exercise, and this did activate the largely-catabolic AMPK-PGC-1alpha pathway that leads to mitochondrial proliferation. One could find fault with the experimental methods, but the findings of the article are very much consistent with my sense of the stark differences between the effects of resistance exercise/strength training and the effects of endurance exercise. There's a lot of other research showing that the activity of mammalian target of rapamycin enzyme(mTOR), a serine-threonine kinase, is negatively regulated by AMPK and hence by the increase in the AMP/ATP ratio [Roe et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16763896)] that tends to occur as a result of endurance exercise. Resistance exercise can also lead to an increase in AMPK activation in the short term, but the long-term effects are quite different from those of endurance exercise. The point is that cell growth, as discussed by Atherton et al. (2005), does not occur in response to the same intracellular conditions (or in response to the same stimuli) as mitochondrial proliferation ("biogenesis") occurs under.

HMB (3-hydroxyisovalerate) increases the phosphorylation and activity of mTOR, by an unknown mechanism [one of multiple articles showing this: Eley et al., 2007: (http://ajpendo.physiology.org/cgi/content/full/293/4/E923)(http://www.ncbi.nlm.nih.gov/pubmed/17609254)], but that's mainly interesting because HMB seems to act, largely or partly, by increasing the plasma membrane or intracellular cholesterol concentration in myocytes and other cell types. It's possible that it's more of a ketogenic substrate than a cholesterol "precursor," given that leucine is known to be ketogenic in astrocytes and hepatocytes and other cell types. I'm not that interested in HMB, because, in my opinion, the potential for problems with phosphate and calcium homeostasis, as a result of calcium salts of HMB that have to include added phosphate, etc., is not a great thing. But it would be interesting to know what the mechanism would be for the increase in mTOR activity in response to HMB. I guess some of the in vitro research would tend to argue against ketogenesis as a primary mechanism, but I would expect that to be one mechanism in vivo. I've suggested other mechanisms in past postings (acylation of proteins or histones by 3-hydroxyisovaleryl-CoA, etc.), but it seems as if the cellular cholesterol concentration might regulate AMPK by some mechanism in extrahepatic cell types. Or it might be that HMB decreases AMPK activity and thereby increase cholesterol biosynthesis, in addition to its role as an HMG-CoA precursor. Alternatively (but not by a mutually-exlusive mechanism), HMB might increase the cellular cholesterol levels in myocytes and, as a result of the feedback inhibition of HMG-CoA reductase activity by that cholesterol, spare acetyl-CoA for entry into the TCA cycle, etc.