Page 10 - ITPS-8-2

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

energy reserves through several mechanisms. These include neurotrophic factor (BDNF) were found following short-
the presence of glycogen in muscles, a high number of term treatment. 45
mitochondria that facilitate the utilization of fatty acids as A hypothesis suggesting that chronic treatment does
an energy source, and extensive vascularization to ensure not provide benefits supports the idea that prolonged
efficient nutrient and oxygen delivery during physical use increases cytokine levels, leading to the onset of
activity. In addition, the use of AMPK modulators an inflammatory process followed by oxidative stress.
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decreases insulin resistance in skeletal muscles and allows Based on these observations, it can be stated that AICAR
glucose utilization as an energy substrate by translocating improves physical effort parameters, but only with short-
the GLUT4 to the cell membrane. In terms of regenerative term use. Like AICAR, metformin activates AMPK
and recovery capacity, AMPK also plays a role in responding through an indirect mechanism by blocking complex I of
to muscle inflammatory processes. During the first phase, the respiratory chain, which results in ATP depletion and
M1 macrophages secrete pro-inflammatory cytokines that an increase in AMP levels, with the possibility of similar
result in ROS, which are necessary for muscle recovery. effects. 46
Subsequently, the recruitment of M2 macrophages is
necessary to combat inflammation. Muscle regeneration In conclusion, AMPK is extremely important for the
involves the migration, proliferation, and fusion of regulation of muscle homeostasis with extension to other
myoblasts, as well as their interaction with immune types of cells and tissues by decreasing insulin resistance,
cells, to form myotubules. Combating the inflammatory stimulating mitochondrial biogenesis, and exerting an
process is extremely important, as disruptions can impair antioxidant effect. 28,33,47,48 Table 2 lists the main molecules
the regeneration capacity of the skeletal muscles. In known to activate AMPK and their mechanism of activation.
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degenerative myopathies, an inflammatory response is
commonly observed, similar to the condition seen in muscle 3. Unraveling aging: The interplay between
tissues deficient in AMPK. Both AICAR and metformin AMPK, caloric restriction and autophagy
have shown anti-inflammatory effects, demonstrating One of the most interesting and bold hypotheses, proven by
potential therapeutic benefits in these conditions. 35-37 evidence in some studies, is the “free radical theory”, which

Among the benefits of physical exercise, sports, and suggests that the uncontrolled generation of free radicals is
movement are reduced incidence of cardiovascular the main driving force of biological aging. Following ROS
diseases, cancer, neurodegenerative diseases (Alzheimer’s, accumulation, the senescence process accelerates due to the
Parkinson’s, Huntington’s), and other neurological loss of mitochondrial integrity, resulting from increased
conditions. Neurogenesis in the hippocampal region and membrane permeability. 74-76 In addition, factors such as
increased neuronal plasticity are associated with improved increased adipose tissue and metabolic imbalances trigger
memory and cognitive abilities. However, a direct link inflammatory processes, leading to mitochondrial lesions,
between these benefits and muscle metabolism has not which favors the acceleration of the senescence rate. 77-79
been demonstrated. To mimic the effects of physical As aging is an inevitable (temporary) process that is
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activity, compounds have been developed and extracted characterized by the loss of tissue functionality and an
that activate regulatory pathways and stimulate genes increased risk of age-related diseases, the use of AMPK
involved in skeletal muscle remodeling. 39-41 However, from modulators is an alternative. Studies suggest the activation
an ethical perspective, this raises the question of whether of AMPK is associated with increased life expectancy
such modulators of physical movement might open the by maintaining cellular homeostasis, enhancing stress
door to controlled forms of sports doping. resistance, and promoting apoptosis and autophagy.

AICAR is known to promote angiogenesis and Thus, activation of AMPK in Caenorhabditis elegans and
vascularization by inducing vascular endothelial growth rodents has been shown to extend lifespan, with numerous
factor gene expression, similar to the effects of physical studies in C. elegans suggesting a possible link between
exercise. 42,43 In doses of 500 mg/kg administered to small, AMPK activation and caloric restriction. Irregularities
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young, and adult rodents for 1 and 2 weeks, respectively, in mitochondrial dynamics with abnormal mitochondrial
AICAR improved spatial memory and coordination. morphology are key characteristics of aging and play
These effects are unlikely to result from direct central a significant role in the development of various age-
effects, as AICAR is poorly permeable to the blood-brain related neurodegenerative diseases, including Alzheimer’s
barrier. Notably, treatments longer than 14 days in young disease and Parkinson’s disease. 81-83 In an animal model
mice do not provide any neuronal benefits. However, of Parkinson’s disease induced in mice, treatment with
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central effects have been observed in the hippocampal metformin (500 mg/kg) for 21 days increased the level
dentate gyrus, where increased levels of brain-derived of BDNF and reduced oxidative stress in the substantia

Volume 8 Issue 2 (2025) 4 doi: 10.36922/itps.4852