A salient response to endurance exercise training is an increase in whole-body maximal oxygen uptake (V˙O2max) and/or an increase in peak V˙O2 of the muscles engaged in training. Since the pioneering work on rat skeletal muscle (12) and later confirmed in humans (40), it has been recognized that endurance exercise training induces skeletal muscle adaptations, leading to enhanced mitochondrial oxidative enzyme activity and O2 consumption (Vmax) by the electron transfer system. The training-induced upregulation in mitochondrial volume and Vmax of respiration is well documented by morphological studies and functional observations at the level of single mitochondrial enzymes and whole mitochondria. In healthy humans, Vmax of mitochondrial oxidative phosphorylation (OXPHOS) is in excess of O2 delivery during whole-body exercise (5), and increases in V˙O2max with training are linked primarily to improved oxygen delivery and expansion of capillary volume, allowing for greater O2 diffusion (and extraction). Accordingly, there is strong evidence to support the hypothesis that, in healthy humans, muscle mitochondrial respiratory capacity poses no limitation to V˙O2max and always retains excess capacity over O2 delivery. However, changes in mitochondrial volume and regulation play a major role in enhancing submaximal endurance performance. In this review, the effect of endurance training on both morphometric and regulatory adaptations of mitochondria will be covered in the context of bioenergetic responses to dynamic exercise. Environment exerts an influence on muscle metabolic capacity and performance. Exposure to high altitude reduces maximal oxygen uptake in proportion to the lower O2 delivery to the muscle while muscle mitochondrial OXPHOS capacity is downregulated across time. Exposure to extreme cold also diminishes muscle mitochondrial OXPHOS capacity, yet the underlying mechanisms and patterns of acclimatization differ from those at altitude.
Skeletal Muscle Mitochondrial Ultrastructure and Location: Effects of Endurance Training
Mitochondria often are illustrated as isolated oval- or bean-shaped organelles, yet their structure in skeletal muscle is now considered a complex branching or reticular network (Fig. 1). From electron microscopy imaging of biopsied muscle, mitochondria are represented several ways in the literature: mitochondrial area, number of mitochondria per fiber, or as a percentage of muscle area or volume density across numerous serial sections (length). Mitochondria also have been classified by location. Subsarcolemmal (SS) mitochondria are located in close vicinity to the cell membrane, often are expressed relative to the surface area of the fiber, and represent about 10% of total mitochondria. Interfibrillar mitochondria (IMF) are located in the fiber center (IMFC), that is, between the myofibrils or in superficial regions (IMFS) — distal to the center of the skeletal muscle fiber. Each fraction constitutes approximately 20% and 70% of the total mitochondrial pool, respectively (28). How closely these fractions reflect the reticular volume (Fig. 1) remains to be ascertained. Mitochondrial volume density generally is considered to be highest in Type I fibers and lowest in Type IIx fibers, typically about 6% and 3%, respectively (33), although volume fractions of up to 11% have been reported for elite cyclists (16). More recent work indicates that Type IIa fibers can possess equally high or even higher mitochondrial volume as Type I fibers (4).
Early work demonstrated a 40% increase in mitochondrial volume density in previously untrained subjects after 6 wk of rigorous endurance training (14), and the increase was somewhat more pronounced in Type IIa compared with Type I and Type IIx fibers (15). The relative increase in the different mitochondrial subpopulations may not necessarily be uniform, and from initial studies, it was concluded that endurance exercise training preferentially increased the smaller-volume fraction of SS mitochondria. In a recent study, SS area (in square micrometers) remained unchanged after 12 wk of endurance training, whereas IMF increased (9). When expressed as mitochondrial area density (in percent), both SS and IMF were enhanced. This contrasts a previous report (28) where overall mitochondrial volume density was increased after 10 wk of endurance training because of an enlarged SS mitochondrial volume density, whereas IMFC and IMFS were both unchanged. Taken together, it is concluded that SS and IMF both increase with endurance training but that SS regions may be more responsive. Imaging advances are making it possible to generate three-dimensional images that may enhance the precision of volumetric changes with training (Supplemental Digital Video, http://links.lww.com/ESSR/A10). Furthermore, three-dimensional electron microscopy images can be merged with fluorescence to illustrate structural/regulatory markers of interest in relation to mitochondrial morphometric quantification.
The Effect of Endurance Training on Mitochondrial Oxidative Capacity and Function in Healthy Humans
Using 31P-MRS methodology, it has been demonstrated that physically active subjects possess higher mitochondrial respiratory capacity (Vmax) than untrained subjects (24) and that Vmax is even higher in endurance-trained elite athletes (21,29). These findings have been substantiated by respirometric assessment of Vmax (or OXPHOS) in muscle samples obtained from vastus lateralis muscle where active trained and elite endurance athletes all demonstrate higher values than those observed in untrained or sedentary subjects (6,19,27,38,42). Elite endurance-trained subjects have about 80% higher Vmax than physically active untrained subjects (19). Although signals governing mitochondrial biogenesis are induced rapidly after acute exercise and short-term training, the type and intensity of training are important factors for inducing overt increases in mitochondrial volume and OXPHOS capacity. In longitudinal exercise training intervention studies in sedentary subjects, an increase in Vmax of 36% with 8 wk of interval exercise (6) or 40% with 6 wk of combined continuous and interval exercise has been found (38) but, quite surprisingly, not with more conventional endurance exercise training (4,6). An increase in skeletal muscle mitochondrial respiratory capacity has been shown after only 14 d of high-intensity interval training (18) similar to that observed after 10 wk of training (30). This is in contrast to low-intensity endurance training where peak muscle V˙O2 increased after 5 wk of ski training because of a higher capillary volume, blood flow, and O2 diffusion capacity at an unchanged mitochondrial OXPHOS capacity (4). Overall Vmax of OXPHOS increases with exercise training, but variable responses occur with different training regimens and the intensity × duration required for such adaptations.
Because OXPHOS capacity and mitochondrial volume density are higher in trained than untrained individuals and because both also may increase with exercise training, it is thought generally that the increase in OXPHOS capacity is accounted for by increases in mitochondrial volume density. Consistent with this view, cross-sectional studies including athletes and inactive subjects demonstrate that, although OXPHOS of muscle is higher in trained subjects, muscle OXPHOS remains unchanged when normalized to citrate synthase (CS) activity (a marker for mitochondrial volume) (27,36). This pattern is consistent with several longitudinal studies showing an increase in OXPHOS after training proportionate with enhanced mitochondrial volume density (18,19,38). In contrast, a recent cross-sectional study on permeabilized fibers reported that mitochondria from trained to very trained subjects had a higher respiratory capacity per unit volume of mitochondria when compared with less fit individuals (19). Part of this discrepancy might relate to differences in experimental design, substrates, and tissue preparation–isolated mitochondria compared with permeabilized fibers. The permeabilized fiber preparation has the advantage that respirometry measures are translatable more directly to the unit mass of muscle in vivo, and muscle structures including the cytoskeleton remain intact, which is known to affect the regulation of mitochondria. Some disadvantages include the need for artificially high [O2] to sustain respiration, diffusion and substrate transport limitations, as well as the presence of cellular enzyme complexes (e.g., ATPases) that can limit the control of experimental measures (e.g., P/O ratio, O2 kinetics). Isolated mitochondria are advantageous in that purely mitochondrial components can be studied (e.g., O2 diffusion P/O ratio, O2 kinetics, transporters); however, partial yield of the total mitochondrial content in muscle (<50%), as well as loss of cellular mechanotransduction and other regulatory signals, may present limitations.
REGULATORY CHANGES IN MITOCHONDRIAL FUNCTION
Oxidative phosphorylation encompasses the final bioenergetic steps in fuel catabolism by which stored chemical energy is trapped as adenosine triphosphate (ATP). The system is under feedback control by the energetic state where increases in adenosine diphosphate (ADP; the major signal), inorganic phosphate (Pi), and creatine/phosphocreatine ratio (Cr/PCr) provide the signals that activate OXPHOS. During contraction, ATP and creatine phosphate are used, resulting in increases of the products ADP, Pi, and creatine. Glycogenolysis and glycolysis are activated by the same signals that activate OXPHOS (i.e., ADP–adenosine monophosphate and Pi). During low- to moderate-intensity exercise, the parallel control of OXPHOS and glycolysis by energy state ensures a balanced supply of mitochondrial substrate in the form of pyruvate. However, during higher workloads, the response to signals is higher for glycolysis than for OXPHOS and there is a spillover of pyruvate to lactate. Reduced oxygen availability will add further imbalance to the system.
In the trained state with more mitochondria, a given exercise load and, therefore, energy demand require a lower OXPHOS rate (i.e., ATP production per mitochondria). Thus, a given ATP production demand for contractile activity occurs at a lower concentration of ADP, adenosine monophosphate, and Pi and results in less activation of glycogenolysis and glycolysis. Accordingly, a primary mechanism accounting for the lower lactate production at a given load after training is an increased mitochondrial volume as described already in 1967 by Holloszy (12). In addition to the quantitative changes (more mitochondria), there is evidence that training also affects the sensitivity of mitochondria to the signaling system. Six weeks of endurance training in sedentary subjects decreased the sensitivity of OXPHOS to ADP but increased the effect of Cr/PCr (39). Similar differences have been observed between endurance-trained and untrained subjects (42). The training-induced changes indicate a change to a more Type I fiber control (38).
The efficiency of OXPHOS (i.e., P/O ratio) is an important parameter in bioenergetics and will influence work efficiency, oxygen demand, and, thus, performance. P/O ratio is measured in isolated mitochondria as the rate of ADP supply per rate of respiration and defines the rate of mitochondrial respiration that is coupled to ATP formation. The P/O ratio is higher with carbohydrate compared with fat substrate because of the larger proton motive force generated with NADH with carbohydrates compared with electron transferring flavoprotein with fat. In isolated mitochondria, the P/O ratio measured during either maximal or submaximal ADP stimulation was not different between sedentary and endurance-trained subjects (27), but a decrease in P/O ratio was observed after ultraendurance exercise (10). Supplementation with nitrate or beet red juice has been shown to increase mitochondrial P/O ratio as well as work efficiency, and the mechanism is attributed to reduced adenine nucleotide transporter activity, resulting in lower back-leakage of protons, in association with nitric oxide binding to cytochrome c oxidase that reduces O2 affinity (22). Obviously, P/O ratio is not a fixed parameter but can be affected by nutrition and exercise. An area of interest for future research is the coupling between vascular and mitochondrial effects of training-induced increases in nitric oxide production. One hypothesis is that nitric oxide enhances blood flow distribution to activated fibers and also improves mitochondrial efficiency in the fibers where perfusion is enhanced.
Changes in Substrate Oxidation with Endurance Training
Because of limited CHO stores, fat oxidation is of major importance for performance during long-duration exercise. Fat oxidation is limited by substrate and oxygen availability and by intrinsic muscle factors (mitochondrial volume and quality, transport proteins). Fat oxidation increases with work rate and reaches a peak at 40% to 60% of V˙O2max after which both absolute and relative fat oxidation decreases. Cross-sectional studies show that peak fat oxidation is higher in endurance-trained subjects both when related to absolute and relative work rate (35). The decline in fat oxidation at higher workloads correlates with the increase in blood La (1) and suggests that both are dependent on V˙O2max and mitochondrial Vmax. Using isolated mitochondria, it was shown that relative fatty acid (FA) oxidation correlates with Type I fiber composition but is similar in endurance-trained and untrained subjects (31). In contrast, studies on permeabilized fibers show increased FA oxidation in elite endurance-trained subjects (19) possibly related to a high proportion of Type I fibers. Although the increased peak fat oxidation after endurance training is related primarily to increased V˙O2max and to increased mitochondrial volume, there is evidence that mitochondrial quality also influences FA oxidation. Several studies have demonstrated that training results in increased respiration with FA-derived substrates with unchanged mitochondrial volume (4,19,30). Thus, mitochondrial OXPHOS capacity may increase with training because of both increased mitochondrial volume density and qualitative regulatory adaptations (7,37). How these changes are induced by different training regimens remains to be elucidated.
ROLE OF MITOCHONDRIA FOR INCREASES IN V˙O2max WITH TRAINING
Endurance training increases O2 delivery to muscle through an increase in peak cardiac output, enhanced regional muscle blood flow, and improved distribution of blood in active muscle through an expansion of capillary volume. Because mitochondrial capacity expressed as Vmax of O2 consumed per milligram muscle exceeds the in vivo whole-body V˙O2, a pattern that is retained after training, it is debated how the expansion of mitochondrial oxidative capacity contributes to improving V˙O2max. It is difficult to ascertain the independent contribution of expanded mitochondrial volume to the increase in V˙O2max with training because blood flow and capillary volume also increase. There is no clear evidence that an increase in mitochondrial volume alone (in the absence of increases in flow and/or capillary volume) elevates whole-body V˙O2max. However, the increase in mitochondrial volume and OXPHOS capacity with training seem important when an isolated muscle is engaged in contraction (e.g., one-leg knee extension (KE)) and O2 delivery to muscle is high. Highlighting the large capacity of mitochondria is the finding that peak muscle V˙O2 is approximately twofold higher during KE compared with two-leg cycling, with the main factor being the more than twofold higher blood flow per unit mass during KE.
A relationship between mitochondrial OXPHOS capacity and mitochondrial O2 affinity has been proposed (23). Mitochondrial p50 is the PO2 at which mitochondrial respiration is half maximum and is measured during the hyperbolic decline in respiration at low O2 levels. A lower p50 indicates a higher affinity for O2, which could contribute to a small increase in V˙O2max by decreasing mitochondrial PO2 and increasing the diffusion gradient (V˙O2 = DO2. (PO2 cap-PO2mit)). Whether this regulatory effect occurs with training has yet to be reported.
It is a general assumption that hypoxia stimulates mitochondrial biogenesis, but to date no single study has demonstrated an increase in human skeletal muscle mitochondrial volume density after acclimatization to a high altitude. In controlled studies, it has been demonstrated that training in hypoxic conditions augments the training-induced increase in mitochondrial volume (8,32,41). This finding has contributed to a rationale for training in hypoxia. However, it also has been shown that training one leg during normoxia and the other leg during hypobaric hypoxia at the same relative intensity (i.e., lower absolute workload during hypoxia) blunted the training response during hypoxia (2). Hoppeler and coworkers (13) reported a 25% reduction in mitochondrial volume density after spending several weeks above 5000-m altitude, and 20 yr later, a similar reduction was observed by others (25). The reduction coincided with a concomitant decrease of the regulator of mitochondrial biogenesis, PGC1α. For both altitude studies, however, one limitation is that the biopsies were taken as part of a Himalayan climbing expedition where confounding factors such as extensive weight loss, changes in physical activity, nutritional intake, and cold temperatures may have influenced the results. Some studies quantifying mitochondria-specific enzymes as a surrogate for mitochondrial volume after expedition style altitude exposure report no change or small losses depending on physical activity level while at altitude (11,25,26). In contrast and in controlled settings (matched diet, physical activity, and ambient temperature), 7 to 9 d of exposure to 4559-m altitude resulted in a reduction of several mitochondria-specific enzymes, as assessed by proteomics. At the functional level, OXPHOS was reduced by approximately 10% after the previously mentioned days spent at 4559 m (17), and a longer exposure (1 month) to 3450- m altitude in equally controlled conditions led to a diminished mitochondrial respiration in complex I and II and maximal OXPHOS without change in mitochondrial CS or cytochrome oxidase enzyme levels (20). It remains to be determined whether the reduction in mitochondrial OXPHOS capacity at high altitude is mediated by reduced activity level and the absolute intensity at which one can train or regulated by an independent mechanism. An important finding with potential implications for performance is that, despite a lower mitochondrial Vmax at altitude, overall mitochondrial coupling efficiency, defined by a lower leak respiration relative to OXPHOS, is improved at altitude (20). Because the magnitude of reduction in O2 delivery to muscle during exercise is far larger than the drop in mitochondrial capacity, the downregulation of mitochondrial capacity may be advantageous for performance at altitude. A lower OXPHOS capacity theoretically would lower the leak respiration and also result in a better matching between mitochondrial capacity and oxygen delivery. This would keep tissue PO2 at a level where respiration begins to become limited by oxygen supply while maintaining a steep O2 gradient from the capillaries to the mitochondria.
There is evidence that muscle function and muscle bioenergetics are impaired in the cold. The aerobic energy cost (V˙O2) at submaximal cycling intensities is elevated, as is muscle lactate accumulation (3), whereas V˙O2max is reduced by approximately 6% in individuals with an average and a high V˙O2max (34). A recent study examined arm muscle mitochondrial function before and after a 42-d skiing expedition in the arctic in temperatures ranging from −45°C to −15°C from beginning to end of the expedition (4). Despite skiing for 6 h d-1, maximal OXPHOS capacity was unchanged in the arm muscles after the expedition. Mitochondrial fat oxidation capacity increased relative to total OXPHOS capacity, indicating a regulatory change in mitochondrial function. As with high altitude, in extreme cold, the adaptive response of mitochondria to training may be diminished by a lower absolute intensity at which one can train. However, acclimation to the cold in combination with training and clothing seems to allow V˙O2max to recover at least in moderately cold temperatures of winter and does not seem to impact training responsiveness in elite cross-country skiers.
SUMMARY AND FUTURE DIRECTIONS
In this review, we have covered general patterns of mitochondrial responses to training and extreme environments. It has been long known that mitochondrial volume is expanded with exercise training, and this alters metabolic regulation during submaximal exercise. Training volume and intensity appear key factors for stimulating mitochondrial volume expansion, yet threshold levels for this response remain to be clarified and with consideration of initial training or fitness level. In this regard, we need a better understanding of the regulation and functional significance of resistance or explosive-type training for stimulating mitochondrial biogenesis. An emerging concept is that mitochondria form a reticular network in skeletal muscle and, in addition to an upregulation of volume, there also are qualitative regulatory adaptations to training and environment (Fig. 2). It remains to be elucidated how mitochondrial ATP production can be upregulated for a given volume of mitochondria after training. Along these lines, the regulatory mechanism for the increase in mitochondrial FA oxidation for a given mitochondrial volume with training is still not well defined. We have covered feedback regulation of mitochondrial function (e.g., ADP), yet much needs to be learned of feed-forward regulation (e.g., by intracellular calcium) during exercise and the impact of training. Environment and climate alter mitochondrial responses to exercise and training, yet the underlying mechanisms are not known. Mitochondrial efficiency has been described based on in situ measurements of P/O ratio and leak relative to coupled respiration, and the significance of these responses in vivo for health and exercise performance remains to be elucidated.
This work was supported by The Swedish National Centre for Research in Sports. The authors thank Michael Larsen, Core Facility for Integrated Microscopy, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, for the three-dimensional reconstruction in Figure 1.
The authors declare no direct funding sources for this work and no conflicts of interest.
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