An integrative approach to the regulation of mitochondrial respiration during exercise: Focus on high-intensity exercise

Abstract

During exercise, muscle ATP demand increases with intensity, and at the highest power output, ATP consumption may increase more than 100-fold above the resting level. The rate of mitochondrial ATP production during exercise depends on the availability of O₂, carbon substrates, reducing equivalents, ADP, P_i, free creatine, and Ca²⁺. It may also be modulated by acidosis, nitric oxide and reactive oxygen and nitrogen species (RONS). During fatiguing and repeated sprint exercise, RONS production may cause oxidative stress and damage to cellular structures and may reduce mitochondrial efficiency. Human studies indicate that the relatively low mitochondrial respiratory rates observed during sprint exercise are not due to lack of O₂, or insufficient provision of Ca²⁺, reduced equivalents or carbon substrates, being a suboptimal stimulation by ADP the most plausible explanation. Recent in vitro studies with isolated skeletal muscle mitochondria, studied in conditions mimicking different exercise intensities, indicate that ROS production during aerobic exercise amounts to 1-2 orders of magnitude lower than previously thought. In this review, we will focus on the mechanisms regulating mitochondrial respiration, particularly during high-intensity exercise. We will analyze the factors that limit mitochondrial respiration and those that determine mitochondrial efficiency during exercise. Lastly, the differences in mitochondrial respiration between men and women will be addressed.

Keywords: Fatigue; High-intensity exercise; Mitochondrial respiration; Oxidative stress; Sprint performance.

Graphical abstract

Fig. 1

Oxygen delivery (A) and consumption (VO₂) (B) during sprint exercise in men. Oxygen delivery and VO₂ were measured by the direct Fick method during 30-s all out sprints in normoxia (red circles) and severe acute hypoxia equivalent an altitude of 5300 m above sea level (light blue circles; P_IO₂ = 73 mmHg). The symbol (*) indicates significant differences between normoxia and hypoxia. Leg VO₂ was similar in both conditions despite large differences in O₂ delivery, indicating that at least during the first 15 s O₂ delivery was not limiting mitochondrial respiration when the exercise was carried out in normoxia (modified from Calbet et al. [16]). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Quantification of the relative contribution of several mitochondrial sites to superoxide and H₂O₂production in isolated rat skeletal muscle mitochondria assessed in a media mimicking conditions of rest, mild aerobic exercise, and intense aerobic exercise. The authors applied corrections for H₂O₂ losses due to degradation by mitochondrial matrix peroxidases. Error bars in inverted position denote the propagated errors for each site while regular error bars indicate the propagated sum of these errors. Values are means ± S.E. (error bars) (n = 3–20). Modified from Goncalves et al. [5].

Fig. 3

ADP/ATP exchange in the mitochondria. Mitochondrial creatine kinase (MtCK) forms proteolipid complexes with VDAC and ANT (‘‘contact site complexes’’, top right) or with ANT alone (‘‘cristae complexes’’, bottom left). ADP and ATP tend to accumulate in the intermembrane mitochondrial space (IMS) of the cristae in the vicinity of MtCK, facilitating the rapid resynthesis of ATP. The ATP flowing through ANT is rapidly hydrolyzed to ADP, which is sent back to the matrix by ANT. MtCK catalyzes the synthesis of PCr with the ATP provided by ANT, using the P_i and Cr available in IMS. The resulting PCr is exported to the sarcoplasm by VDAC. Modified from Schlattner et al. [96].

Fig. 4

Schematic representation of sexual dysmorphisms in mitochondrial function. Higher circulating estrogens promote a greater contribution from fat oxidation to the overall energy expenditure in women than in men at the same relative exercise intensity. Compared to men, women exhibit higher serum leptin concentrations, higher insulin sensitivity, and more leptin receptors in muscle, but less ADP sensitivity. Experiments with permeabilized fiber indicate that women skeletal muscle fibers have increased maximal capacity to oxidize fatty acids and lactate. Women display lower mitochondrial p50 (increased mitochondrial oxygen affinity), and greater mitochondrial volume density, respiratory capacity (OXPHOS) and enhanced O₂ extraction capacity when compared with men matched by VO₂max. ADP = adenosine diphosphate; O₂ = oxygen; OXPHOS = mitochondrial oxidative phosphorylation system; p50 = calculated oxygen pressure at 50% of the maximum flux; VO₂max = maximal oxygen uptake.