Exercise,hepcidin,glycogen depletion and iron deficiency

 Hepcidin has been described as the master regulator of iron. Hepcidin impedes GI tract absorption of iron and decreases movement of iron from the macrophages to the bone marrow.In the anemia of inflammation (AI),hepcidin is chronically elevated so that iron absorption and the transfer of iron from macrophages to the bone marrow is significantly decreased. The anemia is in a sense self limited because at some lowered level of hemoglobin the erythropoietic drive is able to counteract the effect of hepcidin so that the hemoglobin does not continue to fall perhaps through the effect of erythroferrone produced by red blood cell precursors. Hepcidin does not play a key role in the typical case of a runner with iron deficiency anemia (IDA) as long as there is no chronic glycogen depletion,So what does glycogen depletion have to do with this?

Strenuous exercise acutely increases the hepcidin level but after several days of exercising at the same level or slightly higher level the hepcidin return to the baseline value. Running,as a prototype of a repetitive  strenuous exercise is associated with iron deficiency and iron deficiency anemia due to loss of iron from the GI tract,sweat and urine and from repeated bout mild,self limited hemolysis combined with an inadequate dietary iron intake.

However, there  at least running scenario in which elevated hepcidin may contribute to  Iron deficiency and even iron deficiency anemia. Repetitive strenuous exercise in a person who is in a significant negative calories balance with glycogen deficiency can result in chronic elevation of hepcidin and decreased iron  absorption .

Dr Aya Ishibashi et al (1) demonstrated in several long distance runners that serum hepcidin level were elevated on day 4  following three days of strenuous exercise done under conditions of limited calorie intake which correlated with reduced muscle glycogen levels. 

The cytokine, IL 6 is known to stimulate release of hepcidin. Keller et al (2) demonstrated that working skeletal muscle activated transcription of IL6 which they said was "dramatically enhanced "with glycogen levels are low. 

A study utilizing exercise regimens  to simulate military exercises (3) also demonstrated that negative energy balance and glycogen depletion was associated with persistent elevation of hepcidin levels.Another military exercise study (4) demonstrate elevated IL  6 and hepcidin at end of a 7 day high energy output military exercise.Glycogen was not measured but most likely the participants were in a negative calorie balance.

1) Ishibashi, A et al Effect of low energy availability during three consecutive  days of endurance training on iron metabolism in male long distance runners. Physiological report vol 8, no 12 e14494 June 2020 

2)Keller, C Transcriptional activation of the IL-6 gene in human contracting muscle: influence of muscle glycogen content. FASEB J 2001 Dec 15 (14) 2748 E pub 201 Oct 29

3)Hennigar,SR et al Energy deficit increases hepcidin and exacerbates decline in dietary iron absorption. J of Clinical Nutrition 113, Feb 2021

4) McClung,JP et al Effects of a 7 day military training exercise on inflammatory markers,serum hepcidin and iron status Nutrition J. 2013 Nov 4  12 (1)