Page 9 - ITPS-8-2

INNOSC Theranostics and
Pharmacological Sciences AMPK in metabolism, energy and aging

Table 1. Activation of the AMPK enzyme complex depending on the intensity and duration of physical exercise
Type of exercise High intensity, short duration Moderate intensity, medium duration Low intensity, long duration
AMPK activator LKB1 CaMKK
AMPK complex α subunit α 2 βγ α 1 βγ
Activated AMPK isoforms α 2 β 2 γ 3 α 2 β2γ 1 α 1 β 2 γ 1
Abbreviations: AMPK: 5' Adenosine monophosphate-activated protein kinase; LKB1: Liver kinase B1; CaMKK: Calcium-calmodulin-dependent
protein kinase.

body mass. These effects are due to the phosphorylation genes involved in gluconeogenesis, including cyclic AMP-
and activation of target genes under the control of regulated transcriptional co-activator 2 (CRTC2) and
AMPK, such as transcription factors and co-activators class IIA histone deacetylases (HDACs). 24,25 This activation
of the p53 gene, cyclic-AMP response element-binding can benefit athletes by enabling more efficient use of
protein, mammalian target of rapamycin (mTOR), and energy reserves and improving their replenishment during
PGC-1α pathways. However, there is also evidence rest and recovery periods.
showing a protective role for AMPK in cancer cells, which Given the role in the regulation of energy consumption
are susceptible to oxidative stress. These events occur and maintenance of carbohydrate and lipid metabolism
because the LKB1-AMPK system helps maintain cellular homeostasis, 26,27 as well as its involvement in mitochondrial
homeostasis under stress. Preclinical studies suggest biogenesis, AMPK is considered a therapeutic target not
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that combinations of agents that activate AMPK produce only in metabolic diseases (diabetes, obesity) but also in
stronger therapeutic effects. Thus, by targeting AMPK, other pathologies. Thus, there are studies in the literature that
the de novo synthesis of fatty acids, a hallmark of several highlight the role of AMPK in suppressing tumorigenesis. 29,30
cancers, can be prevented. A study by O’Brien et al., In addition, AMPK activation induces G1 cycle arrest, an
19
suggests that the combination of metformin and aspirin effect associated with p53 activation, followed by cell cycle
decreases the survival rate of prostate and lung cancer cells. inhibition through p21. It is also important to note that
In vitro studies on cardiomyocyte cell lines reveal AMPK has the ability to protect tumor cells against cytotoxic
translocation of the fatty acid translocase transporter medication and hypoxic conditions. 5
(FAT/CD36) to the cell membrane with increased fatty acid Another important role of AMPK is its crucial role in
uptake and oxidation rates. Other studies state that when autophagy processes, which rely on the catabolic activity of
muscle glycogen stores are low, fatty acid oxidation becomes lysosomes. In this context, AMPK regulates the activity of
more intense. Activation of AMPK during physical effort two proteins involved in the initiation of autophagy, such
inhibits triglyceride synthesis by suppressing glycerol-3- as Unc-51-like autophagy-activating kinase (ULK1) and
phosphate acyltransferase activity. 4,20,21 Moreover, AMPK the phosphatidylinositol 3-kinase catalytic subunit type 3
prevents the incorporation of palmitic acid into ceramides, (PI3KC3/VPS34). 31,32
lipids involved in the generation of reactive oxygen
species (ROS). AMPK is also involved in glucose uptake Last but not least, the role of AMPK in redox homeostasis
through the TBC1D1 protein, facilitating translocation and its involvement in increasing antioxidant activity
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of the glucose transporter GLUT4. It inhibits glycogen should be highlighted. Analysis of a study published in
synthetase, an enzyme that catalyzes an energy-consuming 2008 during the Beijing Olympic Games demonstrated
anabolic process. 22,23 Glycogen is broken down to glucose that AICAR significantly enhanced sports performance by
by glycogen phosphorylase. While it was originally thought increasing the physical endurance capacity of mice, even
that AMPK regulates both glycogen phosphorylase in the absence of prior physical training. Following these
and glycogen synthase, studies show that only glycogen findings, the World Anti-Doping Agency (WADA) was
synthesis is affected. Specifically, glycogen synthesis is notified, leading to the prohibition of AMPK activators,
regulated through phosphorylation of glycogen synthase such as AICAR and their inclusion in the list of “hormones
by the α2 isoform of AMPK. In skeletal muscles, endurance and metabolic modulators”. This raises the question on
training activates AMPK, which favors glycogen synthesis whether all AMPK activators should be included in the list
by increasing glucose uptake and its conversion to glucose- of prohibited substances or is the improvement of sports
6-phosphate, an allosteric activator of glycogen synthase. performance is only correlated with certain activators of
2
This activation can offset the inhibitory effects of AMPK the enzyme.
on glycogen synthase. During feeding after a period of From the perspective of physical exercise, AMPK
fasting, insulin activates AMPK, which in turn influences influences performance, accelerates recovery, and restores

Volume 8 Issue 2 (2025) 3 doi: 10.36922/itps.4852