What is EPO?

lance armstrong, epo, cycling, doping, blood doping

EPO is a well-known performance enhancing drug that is a common form of blood doping. In 2013, disgraced cyclist Lance Armstrong notoriously admitted to using EPO throughout his career.

Following rampant use by endurance athletes, EPO has earned a reputation as a potent performance enhancing drug. EPO is injected into the blood, a common form of blood doping, to increase the red blood cell count and metabolic factors necessary for aerobic exercise. Its popularity with endurance athletes is a reflection of its powerful effects on performance.  EPO is banned by most sports governing bodies. However, EPO naturally plays a role in regulating a myriad of physiological functions and has recently been found to be of clinical importance.

So what is EPO? EPO is short for erythropoietin. Erythropoietin is responsible for triggering erythropoiesis, the production of new red blood cells. The history of its discovery is rather interesting, and was described in a recent review in Cold Spring Harbor Perspectives in Medicine (Erythropoietin, 2013.  Bunn HF).  

Erythropoiesis in response to altitude was discovered in 1890 when Viault observed that his red blood cell count increased dramatically after two weeks in the mountains of Peru. It was not until 1950 that Reissmann and Ruhenstroth-Bauer showed conclusively that hypoxia (low oxygen) conferred erythropoiesis via a factor in the blood. They proved this by connecting a pair of rabbits at the capillary level by overlapping flaps of their skin.  When one rabbit breathed hypoxic air and the other breathed normoxic (sea level air), the result was both rabbits dramatically increased red blood cell production. By 1964, researchers had found that EPO was produced primarily in the kidneys. Actual human EPO was not isolated and purified until 1977. The EPO amino acid sequence was determined in the 1980s.

Regulation of red cell production by Epo. (A) Decreased oxygen delivery to specialized cells in the kidney results in increased expression and secretion of Epo, which circulates in the plasma and stimulates marrow progenitors, thereby increasing red cell production. If the increase in red cell mass relieves the hypoxic signal, Epo expression is down-regulated. (B) Plasma Epo levels (milliunits/mL) in patients with different types of and degrees of anemia and in those with primary erythrocytosis and secondary erythrocytosis. HIF, hypoxia inducible factor; PCV, polycythemia vera.

How is EPO regulated in the body?  EPO is not directly regulated by hypoxia. A factor called Hypoxia-Inducible-Factor (HIF) turns on EPO transcription in response to hypoxia. As a side note, HIF stabilizers are another banned performance enhancing drug. HIF is extremely unstable and therefore undetectable in cells when one is breathing air with sea level oxygen concentration (21%). When oxygen levels are lowered to hypoxic levels, HIF is much more stable due to deactivation of the HIF-specific ubiquitination protein (which labels HIF for degradation). Under hypoxic conditions, HIF binds to the EPO gene and stimulates transcription of EPO mRNA. EPO mRNA is then translated into the EPO protein by ribosomes. In the kidney, the primary location for EPO synthesis, the HIF subset HIF-2 is responsible for triggering EPO mRNA transcription. EPO then stimulates red blood cell production in the bone marrow by binding to its receptor there, EpoR. The figure above shows this negative feedback loop. 

In addition to its role in regulating erythropoiesis, EPO plays a part in regulating a number of other physiological processes. A review published last year highlights the diverse functions of EPO (Epo and Non-hematopoietic Cells: What Do We Know? 2013. Ogunshola OO and Bogdanova AY).

EPO bound to receptor EpoR, biochemical structure

In the nervous system, EPO serves as a neurotrophic factor and provides neuroprotection. Neuroprotection refers to protecting existing neurons from death due to oxidative stress, ischemia or a variety of neurodegenerative diseases such as Alzheimers. Neurotrophic factors promote regeneration of neurons through neurogenesis following an insult such as stroke. Likely as a result of these effects on the brain, EPO has been shown to be a potential therapy for stroke, depression and neurodegenerative disease in animal studies. Unfortunately, limited human clinical studies with cerebral EPO therapy have produced mixed results.

EPO impacts the heart, endothelium and pancreas. EPO is necessary for heart development. EPO has been found to increase the contractile force, but not rate, of the hearts myocardium. EPO attenuates inflammation in the heart. In the endothelium, EPO promotes blood vessel repair. Furthermore, EPO stimulates vessel proliferation and prevents apoptosis of existing endothelial cells. EPO has been found to help restore the function of beta cells in the pancreas of diabetic mice. EPO overexpression in mice has also been shown to increase insulin sensitivity and lower body weight.

In 1989, the FDA approved a synthetic form of EPO, termed Epogen, developed by Amgen for treating anemia. The utility of EPO therapy for patients with pancreatic, cardiovascular or nervous diseases has been debated. Human trials so far have proved inconclusive. Nonetheless, researchers believe EPO has potential to treat a variety of diseases from depression to diabetes. In summary, we use EPO for numerous physiological functions. As anti-doping agencies continue to crack down on blood doping, EPO may become better known as a clinical therapeutic, rather than a notorious performance enhancing drug. In the meantime, just thank EPO for allowing you to exercise at sea level and simply survive at altitude.

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