As expected, at least for MM patients (see, e.g., 21), in our data both MM and McA patients showed a significant interindividual variability for both peak fractional O2 extraction (Fig. 1) and V˙O2peak (Fig. 2). In some patients fractional O2 extraction at peak exercise did not increase (or even slightly decreased) compared with the values observed at rest; these patients were the ones with the lowest V˙O2peak. In a few patients, on the other hand, peak fractional O2 extraction (and V˙O2peak) were substantially normal. The V˙O2peak values observed in the MM and McA patients of our study corresponded on average to approximately 50% of the values obtained in CTRL, confirming a significant impairment of peak oxidative function. Once expressed in METs (multiples of resting energy expenditure), the values obtained in the patients were approximately 5.5 (range, 2.7–9.7), corresponding to a moderate level of physical activity in healthy age-matched controls.
Whereas in MM patients differences in O2 extraction seem related to the “mutation load” in skeletal muscle (percent mutant relative to wild-type mitochondrial DNA) and to the degree of “cellular heteroplasmy” (not all mitochondria in all fibers in all muscles would have the same phenotypic impairment, see (25)), differences in O2 extraction observed among McA patients are more difficult to explain. Typical McA patients have virtually no myophosphorylase activity in muscle (12,23,26,27), thereby preventing any genotype-phenotype correlation. In McA patients the significant variability of the functional impairment (and of clinical signs) could be related to varying degrees of physical inactivity, which may compound the energy limitation attributable to the genetic defect (23), and/or by polymorphism in the gene for angiotensin-converting enzyme, which may modulate the phenotype of the disease (28). The only exception to the general rule of absent myophosphorylase activity in McA patients derives from recent observations (26) of an “atypical” McA presentation, in which a novel intronic splice mutation in one of the two alleles of the PYGM gene allows a minimal myophosphorylase activity and a phenotype which, in terms of oxidative metabolism during exercise and exercise tolerance, is substantially intermediate between typical McA patients and healthy controls.
In any case, in MM and McA patients we identified and quantified by NIRS the metabolic impairment (lower peak fractional O2 extraction), when it was present, and we found it to be significantly correlated with the variable (V˙O2peak) related to exercise tolerance (Fig. 2). All this was obtained by noninvasive measurements, therefore facilitating repeated or serial evaluations. Some of our observations confirmed previous studies, in which the impaired capacity to increase fractional O2 extraction was determined invasively across exercising limbs in patients with a form of metabolic myopathy known as the Larsson–Linderholm syndrome (29), substantially similar to MM, or in MM patients (20). A substantially unchanged fractional O2 extraction during exercise versus rest was also observed systemically, by determining
, either directly by invasive measurements in patients with the Larsson-Linderholm syndrome (29), or by measuring, both in MM (21) and in McA patients (23,26), peak cardiac output (Q˙peak) and V˙O2peak, and by applying equation 2 to conditions of peak exercise.
Although this approach undoubtedly represents a viable option, it should be noted that concerns related to accuracy, reliability and validity have emerged for noninvasive methods to determine Q˙ during exercise in humans, especially during intense exercise (30).
As mentioned above, Figure 2 showed a strong and significant linear correlation between V˙O2peak and peak fractional O2 extraction. Whereas a correlation does not allow establishment of cause-and-effect, if one considers the Fick equation (equation 2) at peak exercise, and after assuming that peak fractional O2 extraction is indeed a proxy of
, it is tempting to conclude that the impaired capacity to increase fractional O2 extraction during exercise was indeed the cause of the lower than normal V˙O2peak. This concept fits nicely with the pathophysiology of the diseases.
Interestingly, in our original study (12) the pathophysiological hallmark of impaired capacity to increase fractional O2 extraction during exercise was not present in a peculiar group of patients, characterized by reduced exercise tolerance (low V˙O2peak) and by other signs or symptoms suggesting a metabolic myopathy (e.g., elevated serum creatine kinase levels, reduced exercise tolerance, muscle cramps or pain after exercise), but in whom a muscle biopsy did not allow a firm diagnosis of any known myopathy (“patient-controls” (12)). In other words, in these patient-controls (not affected by a known metabolic myopathy) the low V˙O2peak and the impaired exercise tolerance were not attributable to an impaired capacity to increase O2 extraction by skeletal muscles. Thus, the proposed NIRS approach could have diagnostic relevance: “positive” results (low V˙O2peak and low O2 extraction) would support the clinical suspicion of a metabolic myopathy, and could induce the clinician to perform a muscle biopsy to obtain a definitive diagnosis.
Going back to the basics of the Fick equation across exercising muscles (equation 1), in patients in whom C(a-v)O2 may barely increase during exercise, with respect to the values present at rest (12), how could the system try to compensate, to increase V˙O2m (and therefore the sustainable work rate) at least to some extent? Algebraically, an answer would be obvious: by increasing the other factor on the right side of the Fick equation, that is Q˙m (or Q˙ at the systemic level), in other words by enhancing convective O2 delivery to the exercising muscles.
And this is exactly what happens in MM and in McA patients: an “exaggerated” (with respect to the V˙O2 level) cardiovascular response (21,23), confirming the original observation by Linderholm et al. (29) in patients with the Larsson-Linderholm syndrome. How to identify, by a simple and noninvasive tool, this exaggerated cardiovascular response? Textbook exercise physiology comes to help in this case as well: the HR response was substantially higher, for the same V˙O2, in MM and in McA patients versus controls (12). And the slope of the HR versus work rate relationship was significantly correlated to the degree of metabolic impairment, as reflected by the incapacity to increase skeletal muscle fractional O2 extraction (see Fig. 5 in Grassi et al. (12)). Interestingly, in a subsequent study by a different group (31) an increased capillarity in skeletal muscles of MM patients was observed, confirming also from a morphological point of view the compensatory mechanism mentioned above: when the system cannot increase O2 extraction, to preserve V˙O2m as much as possible it increases O2 delivery.
The enhanced convective O2 delivery would aim to increase fractional O2 extraction and V˙O2m by increasing PO2mv (see equation 4). In MM and McA patients PO2mit is presumably higher than normal, as a consequence of the impairment of intracellular oxidative metabolism. Thus, an increased PO2mv would be essential in any attempt to increase V˙O2m (see equation 4). Other compensatory mechanisms aimed at enhancing peripheral O2 diffusion could be increases of capillary volume and red blood cells volume in capillaries. As discussed above, these increases could positively affect the DO2 factor in equation 4, and could be indirectly evaluated by the total[Hb + Mb] variable determined by NIRS. As also discussed above, however, this was unfortunately not possible by the CW NIRS instruments which were utilized in our studies.
SPEED OF ADJUSTMENT OF OXIDATIVE METABOLISM DURING METABOLIC TRANSITIONS
The speed of adjustment of oxidative metabolism during metabolic transitions (usually termed “V˙O2 kinetics” [see, e.g., the reviews (32,33)]) determines the size of the O2 deficit and is considered a functional evaluation tool of oxidative metabolism. In normal conditions, whereas the main limiting factor for V˙O2peak or V˙O2max is represented by cardiovascular O2 delivery, analysis of V˙O2 kinetics would be more “peripherally oriented,” in other words, it would be more specifically related to skeletal muscle oxidative metabolism (34). The scenario is presumably different in patients with respiratory, cardiac or other diseases, in which cardiovascular O2 delivery would represent a substantial limiting factor for the kinetics (33,35). In any case, a faster V˙O2 kinetics during constant work rate exercise is associated with smaller O2 deficit, higher V˙O2max, higher “metabolic stability” (36) and higher exercise tolerance. Analysis of V˙O2 kinetics has been widely applied to patients affected by different pathological conditions (14,35,37–41). In patients with chronic heart failure a faster V˙O2 kinetics has been associated with a better prognosis (42).
In a previous study (41), we observed a markedly slower pulmonary V˙O2 kinetics in MM and McA patients versus CTRL and P-CTRL (see above the discussion about the potential diagnostic value of the proposed measurements). In some patients (see, e.g., the McA patient reported in Figure 1 of that article), the V˙O2 kinetics was extremely slow, probably among the slowest ever described in a human subject (see, e.g., Sietsema et al. (43) in chronic heart failure patients).
The time constant (τ) of the monoexponential function which is usually utilized to describe the V˙O2 kinetics:
[yBAS = baseline value; A = amplitude of the response; TD = time delay; τ = time constant] showed a strong hyperbolic relationship with peak fractional O2 extraction determined by NIRS, as well as with V˙O2peak (see upper panels of Fig. 3, redrawn from (41)). In other words, the patients with the slowest V˙O2 kinetics (highest τ) were those with a more pronounced impairment of skeletal muscle oxidative metabolism.
Following the approach suggested by Wüst et al. (45), we have reevaluated the data originally presented in Grassi et al. (41). As expected for a first-order system (33,46), indices of oxidative performance should be linearly related to the rate constant (k) of the function:
with k = 1/τ. We calculated and plotted k values as a function of peak fractional O2 extraction and V˙O2peak, obtaining indeed a strong linear correlation (see lower panels of Fig. 4). The statistically significant linear correlation, with the elevated r2 value, confirm the preeminent role played by skeletal muscle oxidative metabolism in determining pulmonary V˙O2 kinetics, at least in MM and McA patients. Also for the V˙O2 kinetics a substantial interindividual heterogeneity was observed in the patients, and this heterogeneity was closely related to the heterogeneity of the metabolic impairment (Fig. 3).
Confirming the marked responsiveness of V˙O2 kinetics to exercise training (see, e.g., (47,48)), in MM and McA patients a 3-month program of home-based moderate-intensity exercise training obtained a faster kinetics (16). This improvement, which was associated with improvements of other variables of functional evaluation of skeletal muscle oxidative metabolism (see below), was linearly related with pretraining τ values. In other words, greater improvements were described in the more severely impaired patients.
All analyses described above in this paragraph deal with the “fundamental” component of the V˙O2 kinetics (33,46). It should be stressed, however, that also the “slow component” (49) of the kinetics, that is, the progressive increase in V˙O2 occurring after a few minutes during heavy-intensity and particularly during severe-intensity constant work rate exercise, strongly influences exercise tolerance, mainly through its effects on reduced efficiency and fatigue (1). The slow component of V˙O2 kinetics in MM and McA patients, however, will be more proficiently discussed in the section of the article dealing with the effects of exercise training (see below).
The O2 cost of cycling during constant work rate exercise was estimated in MM and McA patients as ΔV˙O2 (V˙O2 at the end of the exercise minus V˙O2 determined during the unloaded pedaling baseline) divided by Δ work rate (41) (after assuming 15 W for unloaded pedaling). In this calculation no discrimination was made between the fundamental and the slow components of the V˙O2 kinetics, and the obtained values represent an estimate of the overall “delta efficiency” of oxidative metabolism during the exercise task, independently from the exercise intensity domain. In both MM and McA patients, the O2 cost of cycling was significantly (by ~50%–60%) higher than in the controls. In both MM and McA the O2 cost of cycling was reduced by training, although the values remained significantly higher than those obtained in the controls, also after the training intervention (see below). Other things (in particular V˙O2peak) being equal, a higher O2 cost of exercise is inevitably associated with a reduced exercise tolerance (1). If we consider that MM and McA patients also have a lower V˙O2peak (see above), these patients are doubly penalized in terms of exercise tolerance, both by the lower V˙O2peak (lower maximal aerobic power) and by the higher O2 cost (lower oxidative efficiency).
INTRAMUSCULAR MATCHING BETWEEN O2 DELIVERY AND UTILIZATION
Another critical issue during metabolic transitions deals with the temporal and spatial intramuscular matching between Q˙O2 and V˙O2. A “weak spot” in this matching resides in the very different morphological and functional organization of muscle fiber recruitment, based on the motor unit, and of microvascular recruitment, based on the “microvascular unit.” Whereas muscle fibers belonging to the same motor unit are sparse within the muscle, and are often localized several centimeters apart (50), terminal arterioles feed through 10 to 20 capillaries approximately 30 contiguous muscle fibers, belonging to different motor units but within a single microvascular unit of approximately 0.1 mm3 of volume (51). In the presence of such an asymmetrical arrangement, the intramuscular matching between Q˙O2 and V˙O2 (in which nitric oxide seems to play a critical role (3)) could obviously represent a problem. According to Segal (51), as motor unit recruitment and metabolic demand increase with exercise intensity, the locus of blood flow control would “ascend” from terminal arterioles to proximal arterioles and feed arteries, which control blood flow to greater portions of the muscle, thereby lessening the asymmetry described above.
In any case, the asymmetry could still lead to a suboptimal intramuscular Q˙O2 to V˙O2 matching during exercise, possibly in pathological conditions, or during metabolic transitions, in which regulatory mechanisms assuring homeostasis are inevitably under a greater stress. During metabolic transitions a suboptimal intramuscular matching between Q˙O2 and V˙O2 could lead to a transient underperfusion of areas of muscles, and presumably to a transient overperfusion of other regions. The resulting Q˙O2-to-V˙O2 mismatch could determine a transiently increased or decreased microvascular fractional O2 extraction. Whereas multi-site NIRS instruments (see, e.g., (52,53)) have investigated the spatial heterogeneity of fractional O2 extraction at a macroscopic level (different sites of the same muscle, or of different muscles), these instruments lack the resolution to investigate the relevant heterogeneity, occurring at a microscopic level. Other sophisticated NIRS approaches include the so-called high-power instruments, allowing to discriminate between deeper versus more superficial portions of muscles (see, e.g., 68).
Does a Q˙O2-to-V˙O2 mismatch, and a transiently increased or decreased fractional O2 extraction, occur during metabolic transitions in physiological conditions? The answer to this question appears to be negative: different approaches to estimate microvascular O2 extraction (54), among which a NIRS-based one (11), suggest indeed a good matching between Q˙O2 and V˙O2, as exemplified by the unchanged (or slightly decreased) fractional O2 extraction usually observed for approximately 10 to 15 s following the transition. To the same conclusion came a study in which the Q˙O2 to V˙O2 ratio was evaluated inside muscle fibers by determining Mb saturation and intracellular PO2 by 1H-NMR (55). On the other hand, a transient “overshoot” of fractional O2 extraction has been repeatedly demonstrated in pathological conditions, such as patients (56) and rats (57) with chronic heart failure, aging rats (58), subjects exposed to extreme deconditioning (bed rest) in normoxia (13) and in hypoxia (17,18). The overshoot of fractional O2 extraction estimated by NIRS (13,17,18) implies an impaired/delayed Q˙O2 to V˙O2 matching, and would represent a “mirror image” of the undershoot of microvascular PO2 described by phosphorescence quenching (see, e.g., 3,57,58). A lowering of microvascular PO2, albeit transitory, would decrease O2 driving pressure for blood to myocyte O2 flux, thereby impairing peripheral O2 diffusion and skeletal muscle oxidative metabolism.
A transient overshoot in microvascular O2 extraction has been described by our group, by utilizing NIRS, also in MM and McA patients (16) (Fig. 4). Thus, a transient intramuscular unbalance between Q˙O2 and V˙O2 belongs, in these patients, to the relatively long list of impairments of skeletal muscle oxidative metabolism which can be relatively easily detected by standard exercise physiology approaches. Even more interestingly, in MM and McA patients the overshoot decreased or disappeared after 3 months of exercise training (16) (Fig. 4), in association with improvements of other functional evaluation variables. In other words, the “transient mismatch impairment” described in MM and McA patients was reversible with training.
THE “SECOND WIND” IN PATIENTS WITH MCARDLE DISEASE
A typical feature of McA patients is the “second wind” phenomenon (59), characterized by a sudden decrease in HR and by an improvement of exercise tolerance occurring after approximately 8 min of exercise. According to Vissing and Haller (60) the second wind is pathognomonic for the disease, and is attributable to an improved delivery of extramuscular energy substrates, particularly glucose and free fatty acids, to working muscles, which would partially compensate for the impaired intramuscular glycogen breakdown.
In a study carried out by our group (15) we demonstrated a second wind phenomenon during the second of two consecutive and identical 6-min constant work rate submaximal exercises, separated by 6 min of recovery. The extent of the improved exercise tolerance during the second bout was impressive, as exemplified by a 37-bpm decrease, on average, of HR during the second bout versus the first one. Textbook exercise physiology says that, for the same absolute work rate, lower HR values indicate a higher exercise tolerance (and, vice versa, higher HR indicate a lower exercise tolerance). In our study the lower HR values (see left panels of Fig. 5) were indeed associated with significant decreases of the RPE scores. In MM patients, on the other hand, no differences in HR or RPE were observed between the first and the second bout of exercise, confirming the specificity of the second wind phenomenon for McA patients.
Considering that many activities of everyday life are characterized by bouts of exercise separated by recovery periods, the results are of interest also from a clinical and practical point of view, and support strategies that are often already employed by McA patients to increase their exercise tolerance: for example, having an exercise preceded by a few minutes of warm-up activities.
Our study (15), moreover, yielded mechanistic insights into the improved exercise tolerance associated with the second wind phenomenon. A slow component of V˙O2 kinetics was present in the McA patients during the first bout of exercise, whereas it disappeared during the second bout (see middle panels of Fig. 5). As mentioned above, the reduced efficiency of oxidative metabolism, which is exemplified by the progressive V˙O2 increase (slow component) during a constant work rate exercise, is intrinsically associated with fatigue (1), and is usually described during heavy-intensity exercise (above the gas exchange threshold) (49), and particularly above the “critical power” (33,46). On the other hand, no slow component, no reduced efficiency and no fatigue are usually described during moderate-intensity exercise (below gas exchange threshold). Thus, in the McA patients of our study the analysis of the V˙O2 slow component tells us that the second wind “transformed” a heavy-intensity exercise into a moderate-intensity exercise, thereby improving exercise tolerance. In MM patients, on the other hand, no effects on the V˙O2 slow component were described during the second bout.
Other measurements further substantiated the improvements in skeletal muscle oxidative metabolism associated with the second wind in McA patients. During the second bout of exercise, for example, fractional O2 extraction slightly but significantly increased during the steady-state of exercise (from 0% ± 5% to 15% ± 2% of the value obtained during the transient ischemia) (15). Moreover, the overshoot in skeletal muscle fractional O2 extraction (see above), sign of impaired intramuscular matching between Q˙O2 and V˙O2 early in the transition, disappeared or was significantly reduced during the second bout (see right panels of Fig. 5). In other words, in McA patients (but not in MM), the first bout of exercise significantly attenuated or eliminated several functional impairments of skeletal muscle oxidative metabolism (elimination of the slow component, increased fractional O2 extraction at steady state, elimination of the O2 extraction overshoot). The end result being an improved exercise tolerance.
EFFECTS OF EXERCISE TRAINING
Moderate-intensity exercise training exerts positive effects both in MM (22,25) and in McA (23,27) patients, putting these diseases in the long list of chronic pathological conditions (5) in which exercise training may have at least in part a therapeutic role. The positive effects of exercise training in patients with metabolic myopathies were confirmed in a study of our group (16), in which we could also identify some mechanisms responsible for the training-induced effects. Several of the impairments of skeletal muscle oxidative metabolism described in the previous sections of the present review were indeed attenuated or eliminated by a 3-month home-based exercise training intervention (4 sessions per week, approximately 1 h per session, each session consisting of stretching, flexibility and balance exercises, followed by 30 to 45 min of moderate-intensity aerobic exercises on a cycle ergometer) (16).
For some of the investigated variables the impairments were only relieved by training, and the values obtained at the end of the training period were still significantly different from those observed in control subjects. V˙O2peak, peak fractional O2 extraction, the fundamental component of the V˙O2 kinetics, the O2 cost of cycling are typical examples of this pattern of response. The impairments of these variables, therefore, seem to be intrinsically associated with the diseases, and can be only partially relieved by exercise training (or by the second wind phenomenon in McA patients).
For other variables, on the other hand, training substantially eliminated the impairment. Examples are the slow component of the V˙O2 kinetics in McA, and the overshoot of fractional O2 extraction in both patient populations. These impairments, therefore, do not seem to be intrinsically associated with the diseases, but appear to be a consequence of the reduced level of habitual physical activity often associated with the diseases. Interestingly, in McA patients, the second wind phenomenon virtually eliminated these impairments as well.
In our study (16), the habitual level of physical activity was estimated by calculating the total energy expenditure during three consecutive days, by a standard method (61), before and 3 months after the termination of the training intervention. Disappointingly, total energy expenditure was not different after versus before the training period, and the values were similar to those obtained in previous studies on patients with metabolic myopathies (62), corresponding, according to standard classifications (63), to a low level of habitual physical activity. In other words, although it increased exercise tolerance, the adopted training program did not increase the habitual level of physical activity of the investigated MM and McA patients. According to Jeppesen et al. (64) in patients with metabolic myopathies the positive effects of exercise training substantially disappear when the specific training protocol is interrupted. It may be hypothesized that to increase the level of habitual physical activity-specific interventions at a “motivational” level should be implemented (65).
The relevance of translational medicine (bringing basic science methods and tools “to the bed of the patient”) is universally recognized. Too often, however, the tools to be applied translationally are considered to derive only from the “-omics” (genomics, proteomics, transcriptomics, metabolomics, etc.) world. The general failure of this “reductionist” approach is now widely recognized (66). In the present review, we provide evidence of studies demonstrating that scientifically sound mechanistic insights into diseases, interesting and relevant both from a basic science point of view and in clinical/practical terms, and ideally suited to be utilized within a translational medicine approach, can be obtained also from the established field of exercise physiology. More specifically, we suggest high-resolution physiological phenotyping methods developed over the years with the aim to identify and evaluate basic physiological mechanisms, and originally applied for the functional evaluation of athletes and sport performance, which can have a valuable translational application in patients with metabolic myopathies. Advantages of the proposed methods include their noninvasivity (facilitating repeated or serial evaluations), quantitative results, and their focus on one of the main determinants of the patients’ clinical picture and quality of life, that is exercise tolerance, defined as the capacity to produce/maintain adequate muscle force or power to accomplish a task commensurate to the needs of everyday life, of working or leisure activities (1). In cardiac patients exercise tolerance has also a substantial prognostic relevance (2); future studies may help to define if this concept applies also to patients with metabolic myopathies. The general message of the review however, is to provide examples in support of a simple concept: physiology and physiological research remain the essential link between genes, molecules and clinical care (67). The -omics world may identify concepts and mechanisms, but only physiology can give a meaning to these concepts and mechanisms within the general picture of a human body, healthy or ill.
The authors thank Dr. Harry B. Rossiter for the valuable suggestions on pulmonary V˙O2 kinetics analysis, and all the co-authors who actively and effectively participated to the studies carried out by our group and mentioned in the present review (12,15,16,41); these studies were originally funded by Telethon-UILDM Grants GUP 030534 and GUP 08007.
The authors have no conflict of interest to declare. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification or inappropriate data manipulation.
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Keywords:© 2019 American College of Sports Medicine
MITOCHONDRIAL MYOPATHY; MCARDLE DISEASE; SKELETAL MUSCLE OXIDATIVE METABOLISM; FUNCTIONAL EVALUATION; NEAR-INFRARED SPECTROSCOPY