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  • Exercise Induced Hemolysis, Inflammation

    and Hepcidin Activity in Endurance Trained

    Runners

    Peter Daniel Peeling

    Bachelor of Science (Honours)

    This Thesis is presented for the degree of Doctor of Philosophy at

    The University of Western Australia

    School of Sport Science, Exercise and Health

    2009

  • i

    Well, we knocked the bastard off!

    Sir Edmund Hillary, on first climbing Mount Everest

  • ii

    Statement of Candidate Contribution

    The work involved in designing and conducting the studies described in this thesis has

    been completed primarily by Peter Peeling (the candidate). The thesis outline and

    experimental design of the studies was developed and planned in consultation with

    Professor Brian Dawson, Dr Grant Landers and Dr Carmel Goodman (the candidates

    supervisors). All participant recruitment and management was carried out entirely by

    the candidate, along with the organisation, implementation and performance of every

    experimental trial. The assistance of Dr Dorine Swinkels and Erwin Wiegerinck from

    the Department of Clinical Chemistry (Radboud University, The Netherlands) was

    required to perform the urine analysis of hepcidin, since this laboratory is one of only

    two in the world to measure this hormone. The assistance of Associate Professor Debbie

    Trinder from the School of Medicine and Pharmacology (UWA) was required to gain

    grant funding and to set up this collaboration with the hepcidin analysis team in the

    Netherlands.

    Signed:

    Peter Peeling

    (Candidate)

  • iii

    Executive Summary

    Iron is a trace mineral used by the body in many physiological processes that are

    essential to athletic performance. Commonly, the body‘s iron stores are compromised

    by exercise via several well established mechanisms. One such mechanism is the

    destruction of red blood cells (hemolysis), in response to the mechanical stress and

    circulatory strain of exercise. Although it appears that a force-dependent relationship

    between the heel-strike of the running gait and ground contact exists, the effects of the

    intensity trained at and the ground surface type trained upon have not been documented.

    Similarly, the effects of a cumulative training stress (i.e. multiple daily sessions) has not

    been examined. In addition to hemolysis, exercise also invokes an inflammatory

    response that results in an up-regulation of the cytokine interleukin-6 (IL-6). This

    cytokine is the primary mediator of hepcidin expression, a liver-produced hormone that

    regulates iron metabolism in the gut and in macrophages. The influence of exercise on

    hepcidin expression is relatively unknown, and as such it is possible that this hormone

    may be a mitigating factor implicated in athletic-induced iron deficiency.

    Therefore, the purpose of this thesis was to investigate the effect of different training

    frequencies, intensities and ground surfaces on the hemolytic response. In addition, the

    impact of exercise-induced inflammation on hepcidin expression in the 24 h post-

    exercise was investigated, with the aim of determining whether this hormone may be a

    potential new mechanism associated with athletic-induced iron deficiency. Finally, an

    interaction between hemolysis and hepcidin activity was examined to investigate their

    potential combined effect on iron status in the 24 h post-exercise.

    Paper one of this thesis investigated the time course of inflammatory response, urinary

    hepcidin production and iron status changes in athletes during the initial 24 h after

  • iv

    endurance exercise. Eleven moderately trained athletes (6 male and 5 female)

    participated in three laboratory testing sessions, including a graded-exercise test for

    determination of peak oxygen consumption ( V O2peak) and peak heart rate (HRpeak), a 60

    min trial of running (RUN), including 15 min at 75-80% HRpeak and 45 min at 85-90%

    HRpeak, and a 60 min trial of seated rest (REST). Throughout the RUN and REST trials,

    venous blood and urine samples were collected pre- and immediately post-trial, and

    then at 3, 6 and 24 h of recovery. Serum samples were analysed for IL-6, C-Reactive

    Protein (CRP), serum iron and serum ferritin. Urine samples were analysed for urinary

    hepcidin activity.

    Blood data revealed that three participants were classified as stage 1 iron deficient, and

    consequently were removed from the analysis. For the remaining eight healthy iron

    status subjects, the immediate post-RUN levels of IL-6 and 24 h post-RUN levels of

    CRP were significantly increased from baseline, and also greater than measured in the

    REST trial (p

  • v

    and hepcidin activity experienced during running. For this study, ten highly endurance

    trained male athletes were required to complete a graded exercise test, a continuous 10

    km run on both a grass (GRASS) and bitumen road surface (ROAD) at 75-80% peak

    V O2 running velocity, and a 10 x 1 km intervals running session (INT) on grass at 90-

    95% of the peak V O2 running velocity. During each session, venous blood and urine

    samples were collected pre and immediately post-exercise, and at 3 and 24 h of

    recovery. Serum samples were analysed for circulating levels of IL-6, free hemoglobin

    (Hb), haptoglobin (Hp), serum iron and ferritin. Urine samples were analysed for

    changes in hepcidin activity.

    After running, IL-6, free Hb and Hp levels were significantly greater than pre-exercise

    values in all three conditions (p

  • vi

    implemented of a one session training period (T1), comprising the 10 x 1 km intervals

    session only (T1INT). Venous blood and urine samples were collected pre- and

    immediately post-exercise, and at 3 and 24 h of recovery. Samples were analysed for

    circulating levels of IL-6, free Hb, Hp, serum iron, ferritin and urinary hepcidin activity.

    At the conclusion of both the T1 and T2 interval runs, the free Hb and serum Hp were

    significantly increased (p

  • vii

    Table of Contents

    Statement of Candidate Contribution......................................................................... ii

    Executive Summary................................................................................................... iii

    Table of Contents....................................................................................................... vii

    List of Tables............................................................................................................. xii

    List of Figures............................................................................................................ xiv

    List of Abbreviations.................................................................................................. xvi

    Acknowledgements.................................................................................................... xviii

    Publications Arising from this Thesis........................................................................ xx

    Grant Funding............................................................................................................ xxi

    Chapter 1 Introduction

    1.0 Introduction...................................................................................................2

    1.1 Statement of the Problem............................................................................... 3

    1.2 Aims............................................................................................................... 4

    1.3 Research Hypotheses..................................................................................... 5

    1.4 Organisation and Structure of the Thesis....................................................... 6

    1.5 Significance of the Study............................................................................... 6

  • viii

    Chapter 2 Athletic Induced Iron Deficiency: New Insights into the Role

    of Inflammation, Cytokines and Hormones

    2.0 Abstract.......................................................................................................... 9

    2.1 Introduction.................................................................................................... 10

    2.2 Iron Metabolism............................................................................................. 10

    2.3 Iron Absorption, Transport and Storage........................................................ 11

    2.4 Iron Deficiency and Athletic Performance.................................................... 12

    2.5 Avenues of Iron Loss During Exercise.......................................................... 18

    2.5.1 Gastrointestinal Bleeding................................................................... 19

    2.5.2 Hematuria........................................................................................... 19

    2.5.3 Sweating............................................................................................. 20

    2.5.4 Hemolysis............................

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