The role of exercise and exercise-related factors in the control of mitochondrial oxidative function
Author: Walsh, Brandon
Date: 2002-05-31
Location: Idrottshögskolans aula
Time: 9.00
Department: Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
Abstract
The effects of exercise and exercise-related factors on the control of
mitochondrial oxidative function were investigated in human and rat
skeletal muscle. Oxidative function was assessed through the measurement
of oxygen consumption in chemically permeabilized (skinned) fibers.
Mitochondria in skinned muscle fibers remain in their natural structural
environment, permitting sophisticated mechanisms of respiratory control
to be studied while allowing the surrounding milieu to be manipulated.
Specifically, the acute effects of eccentric and high intensity exercise,
the chronic effects of exercise training, and the role of phosphocreatine
(PCr), creatine (Cr), inorganic phosphate (Pi), and H+ in the control
mitochondrial oxidative function were studied.
Two potentially important metabolites that undergo large changes in
concentration in the intracellular milieu during exercise are Cr and PCr.
While the importance of these metabolites for temporal energy buffering
has long been understood, they also have been suggested to play a role in
spatial energy buffering and in the regulation of mitochondrial function
in vivo. It is known that Cr, in the presence of submaximally stimulating
concentrations of ADP, stimulates respiration in skinned fibers from
oxidative muscle. However, the effect of PCr on oxidative function is
unknown. It was shown for the first time that PCr decreases the
sensitivity of mitochondrial respiration to ADP in skeletal muscle.
Additionally, the role of in vivo concentrations of PCr + Cr in
respiratory control was demonstrated. The rate of submaximally
ADP-stimulated respiration increased two fold when the concentrations of
PCr + Cr were increased from those occurring in vivo at rest to those
occurring during high intensity (HI) exercise.
During HI exercise [Pi] and [H+] can be increased several fold in the
intracellular milieu. Although these metabolites play an integral role in
oxidative metabolism, it has also been suggested that, in high
concentration, they can negatively affect mitochondrial function.
Therefore, the effect of these metabolites on respiration in skeletal
muscle skinned fibers was investigated. It was shown that increased
concentrations of Pi and W, either independently or in combination,
decrease the stimulatory effect of Cr on mitochondrial respiration.
Although these metabolites inhibit the control of respiration by PCr/Cr,
they did not affect maximally ADP-stimulated respiration (Vmax).
In order to study the effects of exercise on mitochondrial function,
respiratory measurements in skinned fibers were performed in an identical
medium prior to and following several types of physical activity. HI
exercise (3 bouts of cycling until fatigue at 130% of V02 max) caused a
transient decrease in the sensitivity of mitochondrial respiration to
ADP. In contrast to previous studies in horse, where Vmax decreased
following HI exercise, the maximal respiratory capacity of skeletal
muscle increased immediately following HI exercise and remained elevated
after 110 min recovery.
Eccentric exercise (EE) has been shown to cause structural damage and
functional impairment in muscle and has been suggested to deteriorate
mitochondrial function. To test this hypothesis, the effect of 30 min of
eccentric cycling on skeletal muscle oxidative function was studied. The
results demonstrate that EE, despite causing a high degree of delayed
onset muscle soreness, does not alter mitochondrial function.
It is well known that endurance training results in an up-regulation of
both oxygen transport capacity and peripheral oxidative potential. In
order to determine more precisely the qualitative and quantitative
effects of endurance training on skeletal muscle oxidative function,
mitochondrial function was assessed in skinned muscle fibers before and
after six weeks of cycle training. After the training period, the rates
of non-coupled and maximally ADP-stimulated respiration were increased by
roughly 40%, whereas the sensitivity of the individual mitochondrion to
ADP decreased. It is concluded that, in addition to increases in
mitochondrial density, important qualitative changes in the control of
mitochondrial oxidation function occur following endurance training.
This dissertation has explained an important mechanism of mitochondrial
respiratory control in skeletal muscle by PCr/Cr and demonstrated an
inhibition of this mechanism by Pi and H+. Additionally, it was shown
that mitochondrial function remains intact or is increased following HI
concentric or eccentric exercise. Following endurance training, the
sensitivity of the mitochondrion to ADP is decreased whereas the total
oxidative capacity of skeletal muscle is increased.
List of papers:
I. Walsh B, Tonkonogi M, Soderlund K, Hultman E, Saks V, Sahlin K (2001). "The role of phosphorylcreatine and creatine in the regulation of mitochondrial respiration in human skeletal muscle. " J Physiol 537(Pt 3): 971-8
Pubmed
II. Walsh B, Tiivel T, Tonkonogi M, Sahlin K (2002). "Increased concentrations of P(i) and lactic acid reduce creatine-stimulated respiration in muscle fibers." J Appl Physiol 92(6): 2273-6 (In Print)
Pubmed
III. Tonkonogi M, Walsh B, Tiivel T, Saks V, Sahlin K (1999). "Mitochondrial function in human skeletal muscle is not impaired by high intensity exercise. " Pflugers Arch 437(4): 562-8
Pubmed
IV. Walsh B, Tonkonogi M, Malm C, Ekblom B, Sahlin K (2001). "Effect of eccentric exercise on muscle oxidative metabolism in humans. " Med Sci Sports Exerc 33(3): 436-41
Pubmed
V. Walsh B, Tonkonogi M, Sahlin K (2001). "Effect of endurance training on oxidative and antioxidative function in human permeabilized muscle fibres. " Pflugers Arch 442(3): 420-5
Pubmed
I. Walsh B, Tonkonogi M, Soderlund K, Hultman E, Saks V, Sahlin K (2001). "The role of phosphorylcreatine and creatine in the regulation of mitochondrial respiration in human skeletal muscle. " J Physiol 537(Pt 3): 971-8
Pubmed
II. Walsh B, Tiivel T, Tonkonogi M, Sahlin K (2002). "Increased concentrations of P(i) and lactic acid reduce creatine-stimulated respiration in muscle fibers." J Appl Physiol 92(6): 2273-6 (In Print)
Pubmed
III. Tonkonogi M, Walsh B, Tiivel T, Saks V, Sahlin K (1999). "Mitochondrial function in human skeletal muscle is not impaired by high intensity exercise. " Pflugers Arch 437(4): 562-8
Pubmed
IV. Walsh B, Tonkonogi M, Malm C, Ekblom B, Sahlin K (2001). "Effect of eccentric exercise on muscle oxidative metabolism in humans. " Med Sci Sports Exerc 33(3): 436-41
Pubmed
V. Walsh B, Tonkonogi M, Sahlin K (2001). "Effect of endurance training on oxidative and antioxidative function in human permeabilized muscle fibres. " Pflugers Arch 442(3): 420-5
Pubmed
Issue date: 2002-05-10
Publication year: 2002
ISBN: 91-7349-227-2
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