Daily injections of the AMP mimetic, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) for 1 month in old mice activates AMP-activated protein kinase (AMPK), increases mitochondrial enzyme content and activity, and restores expression of many genes to youthful levels while reducing the expression of the muscle atrogenes muscle atrophy F-box (MAFBx) and muscle RING-finger protein-1 (MuRF1). These AICAR-driven cellular changes are accompanied by increased quadricep muscle mass and ex vivo EDL force production, along with the prevention of a decline in treadmill running performance over the treatment period, suggesting that AMP mimetics and AMPK activators are likely beneficial in treating age-related dysfunction
Sarcopenia refers to the decline in muscle mass and function that occurs with advancing age. It is driven by alterations in multiple cellular processes. AMP-activated protein kinase (AMPK) is a cellular energy sensor that opposes many age-related changes, making it an attractive target for the treatment of sarcopenia. This study aimed to test the effect of chronic treatment of old mice with the AMPK-activating prodrug, AICAR, on treadmill running capacity and muscle mass, force production, gene expression, and intracellular markers relevant to sarcopenia. Old (23 months) mice were tested for treadmill running capacity, then randomly assigned to receive daily treatment with AICAR (OA; 300 to 500 mg/kg, delivered via subcutaneous injection) or an equivalent volume of saline vehicle (OS) for 31 days. Young (5 months) saline-treated mice (YS) served as controls. Treadmill posttesting was performed after 24 days, and the mice were euthanized after 31 days of treatment. Extensor digitorum longus (EDL) muscles were tested for force generation and RNA sequencing, RT-PCR, and western blotting were performed on quadricep muscles. Treadmill running capacity declined from pre- to posttesting by 24.5% in OS mice. This decline was not observed in YS or OA mice. Quadricep weight was ~8% higher, and tetanic force production by the EDL muscle increased by 26.4% in OA versus OS. These phenotypic improvements with AICAR treatment were accompanied by changes in gene expression in OA/YS versus OS muscles consistent with the “rejuvenation” of gene ontologies associated with connective tissue, neurodegenerative disease, Akt signaling, and mitochondrial function, among others. AICAR increased the mitochondrial markers cytochrome C by ~33%, and citrate synthase by ~22%. Serum insulin-like growth factor-1 levels increased, and Akt phosphorylation tended (p = 0.07) to increase with AICAR treatment. Although protein levels of the mTORC1 signaling pathway intermediate, rpS6, were higher in OA versus OS muscles, the phosphorylation of mTORC1 pathway intermediates was unaffected. On the other hand, gene expression of the muscle-specific ubiquitin ligases Mafbx and Murf1 were reduced with AICAR treatment. AICAR treatment mildly increased/preserved muscle mass and force production and prevented a decline in treadmill running performance in old mice. These effects were associated with altered skeletal muscle gene and protein expression, suggesting improved mitochondrial content and metabolic signaling (particularly through Akt) as contributing factors to the observed phenotypic effects. Our findings support further development of AMPK-activating drugs as a therapeutic strategy for improving age-related organismal dysfunction and sarcopenia.
Open Access Paper:
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fba.2024-00252
Relacionado:
Use as a performance-enhancing drug
In 2009, the French Anti-Doping Agency, suspected that AICAR had been used in the 2009 Tour de France for its supposed performance enhancing properties.[5][6]Although a detection method was reportedly given to the World Anti-Doping Agency, it was unknown if this method was implemented.[7] As of January 2011, AICAR was officially a banned substance in the World Anti Doping Code,[8] and the standard levels in elite athletes have been determined, to interpret test results.
There will always be new drugs, such as the weight-loss drug Aicar, which enables riders to shed up to 7kg and yet still maintain their power output.
What is AICAR?
AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) is a substance produced naturally by the body that stimulates AMP activated protein kinase (AMPK), a protein that regulates metabolism in a variety of ways. AMPK acts as an energy regulator and is activated during exercise or other circumstances that use up cellular energy.
The AMPK-stimulating AICAR can also be synthesized in a lab and is being evaluated in preclinical research and human clinical trials as a therapeutic agent to treat certain metabolic disorders in humans.
How do AICAR and AMPK impact performance?
Once activated by AICAR, AMPK works to make energy more available. For example, it increases the usage of fat for energy and causes cells to make more mitochondria (the cells’ powerhouses or energy creators). AMPK basically ensures that the various tissues in the body don’t run out of energy.
There are many circumstances that activate AMPK naturally, including hypoxia (low oxygen levels during exercise or at elevation), hypoglycemia (low blood sugar with exercise or fasting), the use of cellular energy during muscle contraction, and anything that disrupts energy creation within cells.
The effects of activating AMPK are extremely complex since it is involved in so many different metabolic pathways of the body. To date, the medical community has not found a way to target AMPK in a way that allows for the treatment of diseases in humans, although research has suggested it plays a role in diabetes, heart disease, and cancer.
Why is AICAR on the World Anti-Doping Agency (WADA) Prohibited List?
AICAR is prohibited because it’s an AMPK activator, which are prohibited at all times under the category of Hormone and Metabolic Modulators on the WADA Prohibited List because of their potential performance-enhancing effects.
Are there health risks to using AICAR?
Some articles refer to AMPK activators as “exercise-in-a-pill” in the hope that using an AMPK activator will cause the same changes in the body as exercise. However, the truth is much more complex.
Too much activation of AMPK, or activating it in the wrong tissue, can cause serious side effects, including neurodegeneration, or preventing cells from dividing. The accumulation of naturally-occurring AICAR in the body is also associated with metabolic disorders in humans.
However, AICAR has not been extensively studied in people. For this reason and many others, AICAR is an experimental compound that is not yet approved for therapeutic use in humans and should not be used by any athletes.
Sources:
https://www.sigmaaldrich.com/US/en/search/5-aminoimidazole-4-carboxamide-ribonucleotide
https://www.rndsystems.com/products/aicar_2840
