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Iron Status & Fatiguein theEndurance AthleteShould I get a serum ferritin?
Example Case
RJ Dimeff. Clin J Sports Med 2000
Female college middle-distance runner
CC: Fatigue, abdominal cramping
History, exam, labs unremarkable...
Low Ferritin with a “normal” Hb/Hct
Rx: Ferrous sulfate, iron-rich foods
Slowly gets better
Same song, second verse the following year
Rowland, et al.(1989)
This study was very poorly done...
but was a catalyst for the concept of using Fe++
supplements in endurance athletes
Convenience sample of girl H.S. runners
Pre-season & post-season
Traditional max tests (ramp protocol)
Time to volitional exhaustion
No control of training programs
Fatigue Work-Up
History (>90% in athletes)
Exercise/Rest Provocative or Palliative?
Anxiety & Depression
Meds/Substance Abuse
Exam (<5%)
Infection/Inflammatory/Metabolic
Cardiopulmonary/Neuromuscular
Malignancy (PM/DM)
JL Beard. J. Nutr. 131: 568S–580S, 2001.
Fatigue Work-Up
Labs (5-10%)
CBC
UA
Complete Metabolic Profile
TSH
Consider ECG / CXR / OGTT
Rheum screen
ESR, CK, Rheumatoid Factor, ANA
Overtraining...or maybe Iron?
Definition of fatigue vs endurance
Quantifying fatigue in the physiology lab
Studies of iron supplementation & fatigue
Iron metabolism
Fear & loathing (hemochromatosis)
A (not so) final analysis
What is Fatigue?
Christensen, E.H. 1960. Muscular work and fatigue, in Muscle as a Tissue, eds. K.Rodahl, S.M.Horvath, New York, McGraw-Hill.
Physical fatigue: a state of disturbed homeostasis attributable to work and to work environment.
What is Endurance?
Åstrand, P.-O., Rodahl, K., Dahl, H.A., Strømme, S.B. 2003. Textbook of Work Physiology, 4th edition. Champaign, IL.
No definition of endurance
Physical endurance - GEM definition:
A state of prolonged homeostasis despite elevated levels of external physical work; resistance to physical fatigue.
What is Fatigue?
Characterization of exertional fatigue:
Muscle fatigue = 1/endurance
In situ / In vitro preparations
Multiple parameters needed to quantify
Highly sensitive to independent parameters
N.B.: SERCA the likely final common pathway
What is Fatigue?
Loss of muscle contractility & lusitropy
Highly sensitive to independent parameters:
Tpass
Stimulation frequency (twitch vs tetanic)
O2 supply (ml O2 / min, not just Hb/Hct)
Other (e.g., sympathetic stimulation, pressors)
JL Beard. J. Nutr. 131: 568S–580S, 2001.
JL Beard. J. Nutr. 131: 568S–580S, 2001.
Again, Fatigue is...
Loss of contractility and lusitropy
Highly sensitive to O2 supply
TCA cycle and Ox Phos pathways are not rate-limiting in the O2 transport chain and are in excess capacity,
It is unlikely that skeletal muscle iron-dependent compounds are related to fatigability during exercise
therefore...
OK...What About Humans?
Problem: no good objective measure of “muscle failure”
Volitional exhaustion
Relative intensity a critical factor
Max steady-state (i.e., Vt, [La]4 mM, etc.)
Poor control of non-oxidative energy contribution
Failure of contractility
Rhythmic isometric/isokinetic contractions
Low %MVC, low duty cycle
1 contraction / 5 sec, electrical stimulation, etc.
Fatigue in Humans?
Longitudinal studies are very problematic
Constant O2 supply?
Increase in Hb increases O2 delivery
Constant fitness?
Constant absolute vs relative intensity?
Constant non-oxidative contribution?
Existing studies do two interventions
Training
Iron supplementation
Haas, et al.
Examine effect of Fe++ supplements on running economy
Examine effect of Fe++ supplements and training on virtual time-trial performance
Examine effect of Fe++ supplements on isokinetic contractility of knee extensors (not electrically stimulated)
Examine effect of Fe++ supplements on ventilatory threshold in trained subjects
Haas group. Am J Clin Nutr. 1997. 66:334-341.
Hinton et al., (Haas group). JAP. 2000. 88:1103-1111.
Hinton et al., (Haas group). JAP. 2000. 88:1103-1111.
Hinton et al., (Haas group). JAP. 2000. 88:1103-1111.
Brutsaert et al. (Haas group). Am J Clin Nutr. 2003. 77:441-448.
Brutsaert et al. (Haas group). Am J Clin Nutr. 2003. 77:441-448.
Brutsaert et al. (Haas group). Am J Clin Nutr. 2003. 77:441-448.
Hinton & Sinclair. Eur J Clin Nutr. 2007. 61:30-39.
Iron / Fatigue Research
Difficult studies, but fatally-flawed designs
Hb increases with Fe++ supplements
Little/no control of relative intensity
Various inequalities between groups
Multiple interventions (exercise and Fe++)
Volitional fatigue
Vt effect? - possibly but Vt ≠ fatigue
Iron Metabolism
Could sub-normal iron metabolism contribute to fatigue via non-O2 transport mechanisms?
What does ferritin do, anyway?!
JL Beard. J Nutr 2001; 131: 568S–580S.
JL Beard. J Nutr. 2001; 131: 568S–580S.
Ponka, et al. Semin Hematol. 1998; 35:35-54.
EC Thiel. J Nutr. 2003; 133:1549S-1553S.
Ryter & Tyrrell. Free Rad Bio Med. 2000; 28:289-309.
Ponka, et al. Semin Hematol. 1998; 35:35-54.
Ryter & Tyrrell. Free Rad Bio Med. 2000; 28:289-309.
Smith & Roberts. Clin Chem. 1994. 27:335-440.
Forget About Ferritin?
•Well,...no. It can be dangerous.
Hemochromatosis genotypes (HFE mutations) are highly prevalent in the population - one of the most common congenital mutations.
There continue to be no case-reports of a runner with phenotypic hemochromatosis.
Never is a long time.
Chicharro, et al. Br J Sports Med. 2004; 38:418-421.
Athletes: 50 pro cyclists + 15 “Olympic class endurance runners”(vs only cyclists in Deugnier et al. MSSE. 2002; 34:876-880.)
Forget About Ferritin?
Ferritin gene knockout - lethal in utero
Population prevalence of HFE - 33%
Athlete prevalence of HFE - 50%
• Could the hemochromatosis gene be protective against iron-deficiency in runners?
Non-O2 Transport Fe++?
CNS structures that contain Fe++
Cortex, striatum, cerebellum, thalamus
Fe++ a co-factor in myelination
Dopaminergic regions “affected” ≥15% low
Mesolimbic & striatonigral tracts
Motor control, perception, motivation
Serotonin/Norepinephrine - not affected
A (Not So) Final Analysis
James Beard on iron deficiency:
“Thus, although it is convenient at times to categorize individuals as iron-deficient anemic vs iron-deficient non-anemic, this is not a biological reality”.
A (Not So) Final Analysis
Ian Shrier on iron deficiency:
“Low ferritin with hemoglobin in the mid- to upper normal range is at best a relative indication for iron supplementation: low ferritin with hemoglobin in the low normal range is a stronger, yet still relative, indication for iron supplementation in athletes”.
A (Not So) Final Analysis
Ferritin still could be related to fatigue through CNS-mediated pathways
Motor control
Motivation
Thermoregulation
Other?
Should Runners Take Iron?
All things being equal, if your competitor has a higher arterial O2 content than you, your only hope is that they will have a bad day...
Competitive distance runners should probably take an iron supplement and/or eat iron-containing foods, i.e., red meats, unless not winning doesn’t bother them
Menstruating Women - very low risk of hemochromatosis
Men - also at low risk?
Someday...check a ferritin. If it’s not high, forget about it
(at least while they’re a competitive runner)