Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.
To investigate the consequences of inborn excessive erythrocytosis, we made use of our transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89. We detected expression of human Epo in the brain and, to a lesser extent, in the lung but not in the heart, kidney, or liver of tg6 mice. Although no acute cardiovascular complications are observed, tg6 animals have a reduced lifespan. Decreased swim performance was observed in 5-mo-old tg6 mice. At about 7 mo, several tg6 animals developed spastic contractions of the hindlimbs followed by paralysis. Morphological analysis by light and electron microscopy showed degenerative processes in liver and kidney characterized by increased vascular permeability, chronic progressive inflammation, hemosiderin deposition, and general vasodilatation. Moreover, most of the animals showed severe nerve fiber degeneration of the sciatic nerve, decreased number of neuromuscular junctions, and degeneration of skeletal muscle fibers. Most probably, the developing demyelinating neuropathy resulted in muscular degeneration demonstrated in the extensor digitorum longus muscle. Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy. This model allows investigation of the impact of excessive erythrocytosis in individuals suffering from polycythemia vera, chronic mountain sickness, or in subjects tempted to abuse Epo by means of gene doping.
Heinicke
Katja
K
Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), Switzerland.
Baum
Oliver
O
Ogunshola
Omolara O
OO
Vogel
Johannes
J
Stallmach
Thomas
T
Wolfer
David P
DP
Keller
Stephan
S
Weber
Klaus
K
Wagner
Peter D
PD
Gassmann
Max
M
Djonov
Valentin
V
D000532:Altitude Sickness / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D004300:Doping in Sports; D004921:Erythropoietin / Q000097:blood / Q000235:genetics*; D005260:Female; D006400:Hematocrit; D006801:Humans; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D009420:Nervous System / Q000473:pathology; D010807:Physical Endurance; D011086:Polycythemia / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology
D004921:Erythropoietin