AMPK and the Adaptation to Exercise

Abstract

Noncommunicable diseases are chronic diseases that contribute to death worldwide, but these diseases can be prevented and mitigated with regular exercise. Exercise activates signaling molecules and the transcriptional network to promote physiological adaptations, such as fiber type transformation, angiogenesis, and mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is a master regulator that senses the energy state, promotes metabolism for glucose and fatty acid utilization, and mediates beneficial cellular adaptations in many vital tissues and organs. This review focuses on the current, integrative understanding of the role of exercise-induced activation of AMPK in the regulation of system metabolism and promotion of health benefits.

Keywords: AMPK; adaptive responses; exercise; fatty acid oxidation; glucose uptake; metabolism.

Figure 1

Mechanisms by which exercise-induced AMPK modifies metabolism in skeletal muscle. Phosphorylation of AMPK at Thr172 increases glucose uptake by phosphorylating TBC1D1 and TBC1D4, thus promoting their binding to 14-3-3, which inhibits RAB GAP activity. This leads to increased RAB GTP, which promotes mobilization of GLUT4 to the membrane. AMPK activation also increases FA oxidation. FAs are taken up into the cell by a group of FA transport proteins; FAs are then converted to acyl-CoA and taken into the mitochondria by CPT1 for oxidation. AMPK activation promotes FA uptake by phosphorylating and inhibiting ACC. This inhibits ACC synthesis of malonyl-CoA and prevents malonyl-CoA from inhibiting CTP1, thus promoting FA uptake into the mitochondria and FA oxidation. Lastly, AMPK activation promotes PGC-1α activity, resulting in translocation of PGC-1α to the nucleus, where it functions to promote transcription of mitochondrial genes. Abbreviations: ACC, acetyl-CoA carboxylase; ACS, acyl-CoA synthetase; AMPK, AMP-activated protein kinase; CD36, fatty acid translocase; CPT1, carnitine palmitoyl transferase 1; DRP1, dynamin-related protein 1; FA, fatty acid; FABPc, fatty acid–binding protein cytosolic; FABPpm, fatty acid–binding protein plasma membrane; FATP, fatty acid transport protein; GLUT4, glucose transporter type 4; MFF, mitochondrial fission factor; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; RAB GAP, GTPase-activating protein–bound form of RAB; RAB GDP, guanosine diphosphate–bound form of RAB; RAB GEF, guanine nucleotide exchange factor–bound form of RAB; RAB GTP, guanosine-5′-triphosphate-bound form of RAB; Ser, serine; TBC1D1, TBC1 domain family member 1; TBC1D4, TBC1 domain family member 4; Thr, threonine; ULK1, Unc-51-like autophagy activating kinase 1.

Figure 2

Exercise-induced AMPK activation in cardiac metabolism and function. Phosphorylation of AMPK leads to increased GLUT4 mobilizing to the sarcolemma to increase glucose uptake. AMPK activation also increases autophagy and oxidation of FA. Abbreviations: AMPK, AMP-activated protein kinase; CD36, fatty acid translocase; CPT1, carnitine palmitoyl transferase 1; FA, fatty acid; FABPc, fatty acid–binding protein cytosolic; FABPpm, fatty acid–binding protein plasma membrane; FATP, fatty acid transport protein; GLUT4, glucose transporter type 4; Thr, threonine.

Figure 3

Exercise and AMPK activation in hepatic gluconeogenesis. Exercise increases gluconeogenesis, leading to increased glucose for redistribution to the heart and muscle. Gluconeogenesis is an ATP-consuming process resulting in an increased AMP/ATP ratio that activates AMPK. This leads to PGC-1α activation and increased transcription of gluconeogenic genes. Abbreviations: AMPK, AMP-activated protein kinase; NAFLD, nonalcoholic fatty liver disease; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; P_i, inorganic phosphate; Thr, threonine.

Figure 4

Exercise and AMPK activation in lipolysis and browning of white adipose tissue. Exercise induces lipolysis, resulting in increased FA release as fuel for other tissues/organs as well as reesterification of FA into triacylglyceride. Reesterification is an ATP-consuming process resulting in increased AMPK activation and increased PGC-1α-promoted transcription of thermogenic genes and mitochondrial biogenesis. These metabolic changes lead to adipose browning. Abbreviations: AMPK, AMP-activated protein kinase; FA, fatty acid; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; P_i, inorganic phosphate; Thr, threonine.

Figure 5

Exercise-induced AMPK activation in brain adaptation and neurogenesis. Exercise increases AMPK activity, leading to increased transcription of BDNF that promotes neurogenesis. AMPK also increases mitochondria content while promoting autophagy and inhibiting oxidative stress. Abbreviations: AMPK, AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor; Thr, threonine.