EXERCISE AT HIGH ALTITUDE :ADAPTATION OF OXYGEN TRANSPORT

FROM AIR TO MITOCHONDRIA

Jean COUDERT

Laboratoire de Physiologie – Biologie du SportFaculté de Médecine – Université d’AuvergneCLERMONT-FERRAND, FRANCE

HA ↓ PB ↓ PIO2

PIO2 = PB x 0.2093

Exercise ↑ VO2•

↓ SaO2 ↓ CaO2↓ PaO2 (Hypobaric hypoxia)

! Adaptative responses of the respiratory system

The respiratory system

The oxygen cascade

From Rahn H., 1966

Tissues

Mitochondria

vSL

HA

aA

SL

HA(5500m)

IPO2 (mmHg)

From Pugh et al, 1964

Relationship between VEBTPS and VSTPD and VO2•••

S.L.4600 m5800 m6400 m7400 m

Cardiovascular adaptative responses

VO2 =• Qc ( CaO2 – CvO2)

•

Qc = Qs x HR •

Exercise ↑ VO2•

! In Non-Acclimatized Lowlanders (NALL)

! In Acclimatized LL (ALL) and Highlanders (HL)

" ↓ CaO2 ↑ Qc•

(↑HR)

" CaO2, Qc and HR•

to sea-level values

Cardiac responses during acute hypoxiaand after acclimatization

(4000m) (5800m)ACUTE HYPOXIA ACCLIMATIZED SUBJECT

VO2 (l.min-1)•

Qc (l.min-1)•

HR(b.min-1)

HR max(hyp+norm)

HR (norm max)

HR max(hyp+norm)

From Cerretelli P., PUF edition, 1988

Hematological responses

! Quantitative aspect :

" ↑ of the carrying capacity of the blood

! Qualitative aspect :

" alteration of the oxygen affinity of hemoglobin

# ↑ of the carrying capacity of the blood at HA

↓ PO2 ↑ erythropoietin ↑ erythropoiesis

! ↑ red cell mass

! ↑[Hb] and Hb mass

! ↑ Ht

↑ Oxygen content of arterial blood in an acclimatized subject at 5300 m and at sea level

From Ward M.P. et al, 1989

From Pugh, 1964

Delay between : ↑ erythropoietin and ↑ red cell mass

Days

From Richalet J.P. et al , Science et Sport, 1999

Red cell volume

EPO

From Milledge and Coates,1985

Hematological responses and ethnic differences

From Ward M.P. et al, 1989

↓ Oxygen affinity of haemoglobin at HA ( ↑P50 )

From Hurtado, 1964

Evolution of oxygen affinity of Hb, in LL in LA PAZ (3700m)

From Coudert J. et al, Bull. Soc. Ecophysio., 1977

0.36 ± 0.020.35 ± 0.020.28 ± 0.020.23 ± 0.02ATPmol/mol Hb

1.12 ± 0.081.08 ± 0.040.90 ± 0.050.73 ± 0.052-3DPGmol/mol Hb

29.0 ± 0.528.4 ± 1.028.5 ± 0.826.8 ± 0.9P50 mm Hg

17.9 ± 1.117.6 ± 0.818.1 ± 1.116.8 ± 0.9Hb g/dl

50.6 ± 2.948.6 ± 2.150.0 ± 2.646.7 ± 2.6Ht %

J12J5J2J0

↑Oxygen affinity of Hb (↓ P50 ) at very high altitude, specially on exercise

From Bencowitz et al, 1982

! enhances the loading of O2 in the lung

Concept of optimum haemoglobin concentration at HA and exercise

! Problem of viscosity, when [Hb] and [Ht] are too high

# ↓ cardiac output

# ↑ of arterial pressures (pulmonary and systemic)

# risk of thrombosis

From Winslow and Monge, 1987

optimal values [Hb]18g / dl ? Ht ?

Transport from tissues to mitochondria : classical concepts

Interaction between exercise and high altitude hypoxia

Transport from tissues to mitochondria : new concepts

↓ Cellular PO2 (2-4 mmHg)

during muscular exercise stimulating adaptative responses

# ↑ of PO2 gradient between red cells and mitochondria

# Interaction with myoglobin (P50 ≈ 5 mmHg)

# Stimulation of vascular endothelial Growth Factor (VEGF)

(induction by accumulation of HIF-1α in muscle cells)

HIF-1 α + β

Hémoprotéine oxygène Sensor O2

Hémoprotéine oxygène SensorO2 O2

Phosphorylation des protéines

Factor X

VOIES DE REPONSES A L’HYPOXIE, INDUITES PAR HIF-1

Métabolismeanaérobie

Induction des gènes desenzymes de la glycolyse

Induction du géne dela tyrosine hydroxylase

Induction dugène EPO

Induction dugène vEGF

Angiogénèse Vasodilatation Erythropoïèse Respirationaugmentée

Induction des gènesI-NOS et HO-1

From Coudert J., Urgence pratique, 66, 2004

Comparison of the oxygen dissociation curves for normal human (curve A)and myoglobin (curve B). The P50 values are approximately 27 and 5 mmHg(3.6 and 0.7 Ka) respectively.

Myoglobin

Normal human blood

% Saturation

Oxygen pressure (mmHg)

A

B

50

275

Cellular hypoxia and ↑ of reactive O2 species (ROS)

" Hypoxia induced by exercise ?

" Stimulation of angiogenesis ?Independently of the HIF pathway

# Possibilities actively investigated at present time