Finding a New Way to Turn on the Master Metabolic Switch (Part 1 of 2)

Plato, the Greek philosopher who lived in the 4th century BC, knew something about good health and how to maintain it. “Lack of activity destroys the good condition of every human being,” he declared, “while movement and methodical physical exercise save it and preserve it.” A mere 24 centuries later, we have arrived at the same conclusion¹. 

The mechanistic links between a lack of physical activity and health have finally been uncovered, and center on the master metabolic regulatory enzyme 5' adenosine monophosphate-activated protein kinase, or AMPK.

AMPK – the Metabolic Master Switch 

AMPK can be regarded as a metabolic master switch that determines whether available energy is utilized to meet immediate requirements, or stored for future use. Aerobic exercise generates hypoxia and increasing levels of cAMP in skeletal muscle, and this activates (phosphorylates) AMPK both in muscle and in the liver. Once activated, AMPK “instructs” the body to start burning energy and stop storing it. This entails a broad and coordinated set of responses. 

Specifically, activated AMPK interacts with another gene called MTOR to stimulate autophagy in muscle, a complex process that can be regarded as a form of housekeeping or remodeling². Old cellular elements such as mitochondria and contractile proteins are broken down, recycled, and replaced with new ones. In favorable conditions, which include the availability of appropriate nutrients such as the relevant amino acids, the co-factors for protein synthesis, and sufficient levels of anti-inflammatory elements such as the polyphenols³ and omega-3 fatty acids, resistance or endurance exercise will create positive changes. Resistance exercise favors increased muscle mass, while endurance exercise favors improved capillary networks and more efficient contractile mechanisms⁴. 

Both patterns of autophagy, however, induce mitochondrial neo-genesis and a simultaneous increase in the numbers of GLUT4 receptors on the muscle cell membranes⁵. These changes increase the muscle’s ability to carry out oxidative phosphorylation (i.e., the muscle gets fitter). Related important benefits include restored or improved insulin sensitivity, while increased expression and activity of muscle LPL leads to improved plasma lipid profiles.

If that were all, it would explain only a fraction of the benefits of exercise – but there is more: Activated AMPK increases fat burning via beta oxidation⁴ and inhibits cholesterol synthesis by down-regulating HMG CoA reductase⁶ and fat formation by down-regulating acetyl CoA carboxylase.

The net effects of this AMPK-induced cascade include improved muscular performance, visceral and other fat loss, and the reversal of metabolic senescence^7,8. These benefits of physical exercise are well known. At last we have an understanding of how they are mediated, and why Plato was right.

Tomorrow, I’ll go into the new ways to activate AMPK.

 REFERENCES

1.) Chau JY, Grunseit AC, Chey T, Stamatakis E et al (2013). Daily sitting time and all-cause mortality: a meta-analysis. PLoS One. 8(11):e80000.

2.) Egan B, Zierath JR (2013). Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 17(2):162–184.

3.) Menendez JA, Joven J, Aragonès G et al (2013). Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents. Cell Cycle 12(4):555-78.

4.) Baar K (2006). Training for endurance and strength: lessons from cell signalling. Med Sci Sports Exerc. 38(11):1939–1944 

5.) Burcelin R, Crivelli V, Perrin C et al (2003) GLUT4, AMP kinase, but not the insulin receptor,are required for hepatoportal glucose sensor-stimulated muscle glucose utilization. J Clin Invest 111:1555–1562

6.) Davies SP, Carling D, Munday MR, Hardie DG (1992) Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets. Eur J Biochem 203:615–623 

7.) Calabrese V, Cornelius C, Cuzzocrea S et al (2011.) Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Med. 32:279–304. 

8.) Park SH, Huh TL, Kim SY, Oh MR et al (2014). Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): A randomized, double-blind, placebo-controlled trial. Obesity (Silver Spring). (1):63-71