AMPK and the biochemistry of exercise: implications for human health and disease

Abstract

AMPK (AMP-activated protein kinase) is a phylogenetically conserved fuel-sensing enzyme that is present in all mammalian cells. During exercise, it is activated in skeletal muscle in humans, and at least in rodents, also in adipose tissue, liver and perhaps other organs by events that increase the AMP/ATP ratio. When activated, AMPK stimulates energy-generating processes such as glucose uptake and fatty acid oxidation and decreases energy-consuming processes such as protein and lipid synthesis. Exercise is perhaps the most powerful physiological activator of AMPK and a unique model for studying its many physiological roles. In addition, it improves the metabolic status of rodents with a metabolic syndrome phenotype, as does treatment with AMPK-activating agents; it is therefore tempting to attribute the therapeutic benefits of regular physical activity to activation of AMPK. Here we review the acute and chronic effects of exercise on AMPK activity in skeletal muscle and other tissues. We also discuss the potential role of AMPK activation in mediating the prevention and treatment by exercise of specific disorders associated with the metabolic syndrome, including Type 2 diabetes and Alzheimer's disease.

Figure 1

Activation of AMPK in skeletal muscle during contraction/exercise. Although LKB1, the main kinase acting on α2 AMPK, is thought to be constitutively active, the possibility exists that SIRT1 may regulate LKB1 activity perhaps during prolonged exercise. In muscle, CaMKK may act as an AMPK kinase especially towards α1 AMPK during conditions in which AMP accumulation is limited. The role of TAK1 in muscle is uncertain. Binding of AMP to the γ subunit of AMPK makes AMPK a poor substrate for PP2C resulting in increased net phosphorylation of AMPK. IL-6 produced by contracting muscle may increase AMPK activity in this or adjacent muscle by an as yet unknown mechanism (broken line). The β subunit of AMPK has a glycogen binding domain and high glycogen levels in muscle inhibit AMPK activation during exercise.

Figure 2

During exercise ATP is degraded to ADP. ADP in turn is in part reconverted to ATP and AMP via the adenylate kinase reaction. The AMP/ATP ratio is very sensitive to changes in high energy phosphates because the adenylate kinase reaction is in equilibrium. Thus, [ATP][AMP]/[ADP]² = K and [ATP][AMP] = K × [ADP]². If both sides of the latter equation are divided by [ATP]² we get [AMP]/[ATP] ≈ ([ADP]/[ATP])² indicating that the AMP/ATP ratio varies approximately as the square of the ADP/ATP ratio.

Figure 3

Proposed roles of AMPK in regulation of metabolism and gene expression in skeletal muscle. Although there is clear evidence for these roles of AMPK in resting muscle, proof of this during exercise has so far been difficult to establish unequivocally using genetic mouse models with partial ablation of AMPK activity. See text for details.

Figure 4

Model describing the regulation of protein synthesis by AMPK, Ca⁺⁺ and Akt -signaling pathways. Phosphorylation of TSC2 by Akt induces activation of the Rheb GTPase and the mTORC1 pathway promoting protein synthesis. In contrast, phosphorylation of TSC2 by AMPK results in Rheb inactivation and mTORC1 inhibition. Activated mTORC1 phosphorylates and activates p70S6kinase and phosphorylates and inactivates eEF2kinase (an inhibitor of eEF2), resulting respectively in the stimulation of peptide translation and elongation. In addition, activated mTORC1 phosphorylates 4EBP1 which binds to and inhibits the initiation factor eIF4E. This in turn inhibits 4EBP1 binding to eIF4E and enhances its ability to initiate translation. Thus mTORC1 coordinates the regulation of protein synthesis at the levels of initiation, translation and elongation. Same colours indicate same level in signal transduction.

Figure 5

The Metabolic Syndrome can be defined as a disorder in which combinations of overnutrition, inactivity and as yet poorly defined genetic factors results in a state of metabolic dysregulation characterized by lipid abnormalities, insulin resistance and inflammation. This in turn can predispose to one or more of the shown disorders. Apart from inactivity being a causal factor, exercise has demonstrated efficacy in treating and preventing both the state of metabolic dysregulation and many of the diseases to which it predisposes. See text for details. NAFLD-NASH: non-alcoholic fatty liver disease. PCOS: Policystic ovary syndrome.

Figure 6

Some metabolic syndrome associated disorders that may be improved or prevented by exercise. Exercise, acting at least in part via AMPK, could exert these benefits by improving abnormalities in glucose and lipid metabolism, insulin secretion and action, inflammation, mitochondrial function, angiogenesis and other pathogenic factors.