AMP-activated protein kinase (AMPK)

AMPK plays a central role in the cellular response to metabolic stress. It functions in part by sensing increased AMP levels, an indicator of low energy levels. AMPK is also activated by increased cytosolic calcium^[1] or reactive oxygen species (ROS),^[2] which become elevated during stressful conditions. Although AMPK is often thought of as a regulator of energy homeostasis, more broadly it can be considered as a central control point in the cellular stress-response, sensing and responding conditions such as low energy levels or starvation, hypoxia, or exposure to toxins that inhibit ATP production in mitochondria.

AMPK and protein synthesis

Like mTOR, AMPK functions as a central node in the signaling network that balances anabolic vs. catabolic activity to maintain homeostasis. Whereas mTOR activation turns on anabolic pathways such as protein and fatty acid synthesis, AMPK operates on the flip side of that coin, turning on catabolic pathways such as fat oxidation and autophagy. In the context of muscle building, mTOR is often thought of as the anabolic enzyme, and AMPK as its catabolic counterpart. Given the respective roles of these two enzymes in regulating the anabolic state of any given cell or tissue, it would make sense to keep mTOR activated as long and as much as possible, while limiting AMPK activity. Nothing in the body happens in a vacuum, however, and there is much cross-talk between these two enzymes. Both are important for recovering and adapting from strenuous exercise.

AMPK is particularly important in skeletal muscle, where ATP turnover can increase up to 100 times during exercise.^[3] Cytosolic calcium and ROS also increase during exercise. This increase in metabolic stress activates AMPK, which turns on catabolic pathways to free up more glucose, fats, and amino acids to fuel hard-working muscles. AMPK also signals to mTOR, suppressing protein synthesis.^[4] This makes sense, since protein synthesis requires a significant amount of energy, which is at a premium during exercise. The priority for a muscle during a tough workout is to make available enough energy to fuel hard contractions, not make new proteins. After the workout is over, metabolic stress decreases, AMPK is no longer activated, and mTOR later turns on protein synthesis to for repair, recovery, and adaptation from the exercise-induced damage.^[5]

In addition to ensuring energy availability in skeletal muscle during exercise, AMPK is also an important regulator of autophagy, which is critical for maintaining muscle structure and function. This is illustrated by studies in mice, where knocking out important autophagy-related proteins revealed that autophagy is required to maintain muscle mass.^[6] This may also explain diminished muscle mass and function during human aging, which also coincides with decreased autophagy.^[7]

AMPK and mTOR activity coordinate anabolic and catabolic pathways in skeletal muscle to support the performance, recovery from, and adaptation to exercise.

AMPK in health and disease

Under normal conditions, AMPK and mTOR activity is coordinated to maintain homeostasis and good health. When signaling between these two enzymes becomes out of balance, problems can arise, as illustrated by over-activation of mTOR signaling in obesity, metabolic syndrome, and type 2 diabetes.^[8] This in part drives insulin resistance, impaired glucose tolerance and impaired autophagy- all common features in metabolic disease. Given the reciprocal relationship between mTOR and AMPK signaling, agents that can activate AMPK are a promising area of research. The diabetic drugs metformin^[9] and thiazolidinediones (TZDs) work in part by activating AMPK, increasing glucose uptake and fatty acid oxidation, while decreasing glucose release from the liver.^[1]

Naturally occurring polyphenols such as resveratrol,^[10] quercetin,^[11] genistein,^[12] and epigallocatechin gallate EGCG (a catechin in green tea),^[12] are potent AMPK activators, which may in part drive some of their health-promoting effects. Berberine,^[13] and alpha lipoic acid,^[14] have also been shown to be AMPK activators, which may underly their anti-diabetic effects.

The health-promoting properties of polyphenols, berberine, and alpha-lipoic acid may occur in-part through their AMPK activating ability.