Introduction
AICAR, an amide-conjugated nucleoside, is an analog of adenosine. The international nonproprietary name (INN) of AICAR is acadesine; the full unabbreviated name is 5-Amino-1-(5-O-phosphono-ß-D-ribofuranosyl)-1H-imidazole-4-carboxamide (Chemspider aicar entry. (n.d.), and it is variously referred to as AICA riboside, AICA ribonucleotide, Z-nucleotide, and ZMP (however, it should be noted that ZMP specifically refers to the phosphorylated form – AICA riboside monophosphate – that is converted within cells after administration of AICAR). Its actions are primarily mediated by selective AMPK activation as well as conversion into factors that also act on AMPK.
AMPK: The key to understanding AICAR
In seeking to understand AICAR, researchers are well-served by first understanding AMPK. AMPK, long known to play a role in cellular energy-switching from use of ATP to ADP and AMP as an energy-transfer substrate, has recently (within the past decade) been shown to act as a cellular as well as whole-body energy “sensor” that plays an active and intriguing role in many systemic processes, and of which dysregulation contributes to many disease states.
Because AICAR induces AMPK signaling through a relatively direct pathway, is used in many studies to study and better understand AMPK itself. At the time of writing (2012), however, there are vastly more published inquiries into AMPK than of AICAR specifically; since AICAR’s effects are similar (or identical to) AMPK, it is possible to better AICAR by closely reviewing AMPK studies to infer AICAR’s effects.
AICAR therapeutic uses
The actions of AICAR vary greatly by method of administration, duration of application, and dosage. Administration of exogenous AICAR orally or by injection shows promise for a plethora of medical problems and disease states: ischemia, hypertension, diabetes, obesity, cancer, Alzheimer’s disease, and even aging may be addressed to varying degrees by use of AICAR as a drug (Salminen et al).
Lifestyle factors such as overeating or under-exercising appear to initiate a cascade of pathological events that are mediated by altered AMPK signaling; AMPK expression is associated with exercise and periods of not eating. Other genetic factors also predispose individuals to AMPK dysregulation. Eventual effects of AMPK dysregulation – such as obesity, diabetes, even Alzheimer’s disease – can be treated or even partially reversed by AICAR-induced AMPK expression, whereas diet or exercise may not exert a major effect past an early or undetectable point in the pathology.
Currently, AICAR (under the INN acadesine) is in use as a myoprotective agent: when applied, it protects the heart against myocardial reperfusion (re-introduction of blood-flow) after ischemia (restriction of blood-flow, either acutely or chronically. It is also being researched for treatment of lymphoma.
AMPK acts in nearly all tissues of the body, both as a local cellular energy balance signal and sensor – controlling energy-in versus energy-out pathways in response to changes in other cellular factors and available energy – and as a systemic controller of metabolic state and other non-metabolic processes. AMPK also acts as an important bridge between cellular and peripheral tissue energy regulation and systemic energy regulation. AMPK acts within the master control switch of the body, the hypothalamus, as well as in nearly all types of cells.
Research uses of AICAR peptides
AICAR is useful in researching the purine synthesis pathways and their downstream effects to better interpret biomarkers for different disease states. Most cancer cells rely on the de novo purine synthesis pathway, while normal cells prefer the salvage pathway; many chemotherapeutic drugs inhibit purine synthesis. A better understanding of these differences between cancer cells and normal cells should lead to more-selective less-toxic chemotherapy drugs, as well as better ability to tailor therapies to individuals via improved understanding of biomarkers related to purine synthesis inhibition in various cell types (Boccalatte et al, 2009).
AICAR, AMPK, and purine synthesis pathways
Endogenous AICAR also exists in cells; it is an intermediate in the de novo purine nucleotide synthesis pathway, specifically in the generation of inosine monophosphate (IMP), from which adenosine monophosphate and adenosine triphosphate are generated (Berg et al, 2002). However, as an exogenous AMPK-activator, AICAR does not disrupt AMP-to-ATP ratios within cells. A few of the effects of AICAR administration such as induction of apoptosis in cultured immortalized T-cell lymphocytes, do not involve activation of AMPK (López et al, 2003).
ATP (adenosine triphosphate) acts within the human body as an energy transfer molecule within cells. It is an unstable molecule with high-energy phosphate bonds; when the bonds are “broken” via hydrolysis, the released energy is utilized within cells to do work. ATP breaks down into ADP (adenosine diphosphate) and phosphate. ADP can be further hydrolyzed into AMP (adenosine monophosphate) to release more energy. Shifts in the ratio of ATP to AMP correlate with energy balance; a lower ratio means that less energy is available and/or ATP demand is high due to exercise demand. AMPK inhibits energy- consuming pathways such as protein synthesis and fatty acid synthesis, and upregulates energy-generating pathways such as fatty acid oxidation and glucose transport.
AMPK expression changes according to ATP-to-AMP (and ADP) ratios, which fluctuate according to energy availability. AMPK expression or absence then exerts an appropriate effect according to energy availability: energy storage in times of surplus, energy usage in times of scarcity.
Roles of AMPK signaling in various physiological systems and states
In 2008 AICAR research at the Salk institute in San Diego, California generated headlines like the LA Times article “’Exercise Pill could take the work out of workouts.” The portrayal as a pill can mimic exercise has intrigued the public, despite some factual errors (Bamford et al write “AICAR treatment did not alter the MHC-based fibre type composition in fast- or slow-twitch muscles” (2003) and the 2008 article merely discussed specific gene-expression related to the structural adaptation found in endurance athletes (Narkar et al, 2008)):
"Doping,” the use of pharmacological agents to improve athletic performance for competition, is controversial and intrigues the public mind. AICAR improved treadmill performance in untrained mice by 45% (Narkar et al, 2008), leading to speculation that it may work as a performance-enhancing drug (PED) in humans. Tests have been developed for AICAR use in professional athletes, but since the 2008 articles the medical community has focused on AICAR as a way to better understand the profound role of AMPK in health and disease states and on AICAR as a treatment for a variety of pathologies."
AMPK and mTOR in resistance and endurance exercise
In humans, AMPK is increased in response to both endurance and resistance training, but mTOR response is thought to be specific to resistance training (Vissing et al, 2007). Basal concentrations of mTOR and AMPK were not permanently affected in a study of three groups (control, endurance, resistance training) undertaking ten weeks of training (Vissing et all, 2007). Although Nader speculates (2006) that concurrent endurance and strength training may be counterproductive due to the potential of AMPK (expressed with endurance training) to limit mTOR’s effect, Medeiros et al found that in the rat swimming increases transduction activity of proteins involved in insulin-dependent protein synthesis and the mTOR pathway (2011).
The likely explanation is that presence or absence of factors such as insulin and amino acids is as important an influence on the ultimate physiological outcome of exercise as the nature of the exercise; AMPK expression occurs in a fasted state regardless of nature of exercise, as well as in response to any exercise; mTOR proteins are expressed primarily in a fed state, and in response to resistance exercise – but are unlikely to be expressed in significant quantities if the exercise is performed fasted.
The increased potential for mTOR protein transduction after endurance exercise may be explained by the cross-talk between AMPK and mTOR; AMPK acts as an mTOR control and regulates plasticity of muscle tissue (Lantier et al, 2010). As a therapeutic agent, this suggests that ongoing AICAR use should not significantly disrupt signaling cascades relevant to anabolism provided that insulin and amino acids are present during and after resistance exercise.
In an animal model of obesity, Williamson and Drake (2011) found that two weeks of AICAR administration paradoxically promoted muscle-growth. The authors of the study hypothesize that lower fasting AMPK levels, which relate to insulin-resistance found in obese, aging, or otherwise insulin-resistant muscle tissue, results in an overall lower metabolic capacity of the tissues and therefore a reduction in mTOR effect; normalizing AMPK levels results in a net reduction of mTOR with a surprising effect:
Our recent data show that short-term (2-week), daily treatment of obese (ob/ob) mice with AICAR normalized their hyperactive, fasted-state mTOR signaling. Along with the expected reductions in circulating blood glucose and insulin concentrations, and muscle lipid and glycogen content after AICAR treatment, translational capacity and mass (including muscle fiber areas) of the plantar flexor muscle complex were significantly increased in the obese treated mice. It is our view that the oxidative metabolism/capacity of the muscle and the regulatory processes of muscle growth (i.e. mTOR and translational control) need to be normalized to elicit growth in insulin resistant (e.g. obese, aged) muscle.
Paradoxically, mTOR reduction in certain physiological states by AMPK/AICAR can result in improved protein synthesis and muscle-cross section.
Lantier et al, 2010). AMPK directly inhibits mTORC1, the mTOR complex involved in overloading-induced hypertrophy of muscle cells (Lantier et al, 2010).
Lantier et al tested the effect of total AMPK inhibition in myotubes and found that it resulted in myotubes 1.5 times bigger than AMPK-expressing myotubes. However, the AMPK-deficient myotubes failed to respond to mTOR pathway activation: while they started with an initial greater size, they did not increase in size whatsoever when stimulated with mTOR pathway effectors (Lantier et al, 2010).
One possible explanation is that protein synthesis could not be increased any further and so the mTOR effector had no effect, but another – echoing Drake and Williamson’s 2011 paper – is that AMPK deletion limits muscle growth due to limiting energy-generating capabilities necessary for muscle growth (Lantier et al, 2010).
AMPK also limits cardiac hypertrophy, and AMPK deletion results in cardiac hypertrophy (Lantier et al, 2010), a state probably caused in part by mTOR overexpression.
Fatty acid synthesis and oxidation
AMPK is a master lipid metabolism regulator (Lim et al, 2009): high levels of AMPK inhibit cholesterol and fatty acid synthesis. AMPK also acts as a cellular signal to increase fatty acid oxidation by indirectly increasing levels of carnitine palmitoyltransferase-1 (CPT-1), which is the rate-limiting factor in mitochondrial uptake of free fatty acids (FFAs). In other words, AICAR and AMPK increase the upper limit of the body’s ability to burn stored fat for energy.
Yin finds that AMPK is upregulated in fat cells during beta-adrenergic agonist-induced lipolysis due to intracellular fat level via cAMP increases and greater phosphorylation of AMPK, and AMPK is necessary for optimal beta-induced lipolysis (2005).
AMPK dysregulation is implicated in obesity: lipolysis is inhibited and constant low-grade fatty acid synthesis may take place. A steady caloric surplus (energy surplus) suppresses AMPK, resulting in reduced release of fat for fuel usage, and instead resulting in constant low-grade fat storage.
Direct application of AICAR is likely to result in improved lipolysis and fat oxidation, as well as decreased levels of fatty acid synthesis. This is a revelation for development of future obesity treatment strategies.
Conclusion
AICAR has yet to be realized as a mainstream treatment, likely because wide-range systemically acting drugs with profound cellular and systemic effects are difficult to press into medical use under current the regulatory climate in the United States, Canada, and EU countries; the wide range of effects raises hard-to-answer questions about the safety and appropriateness of AICAR for any given disease, particularly “lifestyle” conditions such as obesity and insulin resistance, which have accepted “lifestyle” remedies of diet and exercise and accepted medical remedies as they reach a certain point in pathology.
In the case of Type 2 diabetes, further animal and human safety and efficacy studies could prove AICAR to be a viable candidate, but the current drug metformin is a viable AMPK-targeting agent; AICAR could also be a financially risky choice for investors with a viable (if perhaps less-effective) similar drug on the market. In the case of Alzheimer’s disease, AICAR may also prove to be a next-generation treatment; a better understanding is needed, though, as AMPK appears to play a role in advancing late-stage Alzheimer’s.
For now, AICAR will continue to be used by researchers to better understand the effects of AMPK (and as a treatment for lymphoma and after cardiac ischemia); doubtless, medical advances will continue to be made due to AICAR’s usefulness as a research aid, regardless of when AICAR itself is brought in as a therapeutic agent for the conditions discussed herein.
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