Exercise testing and prescription in patients with inborn errors of muscle energy metabolism

Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and primary mitochondrial myopathies.


| INTRODUCTION-INBORN ERRORS OF MUSCLE ENERGY METABOLISM (IEMEM)
IEMEM are generally divided into three main groups: disorders resulting from defects in carbohydrate metabolism or lipid metabolism, or mitochondrial disease. Although many of these conditions have been labelled as metabolic myopathies, not all IEMEM lead to myopathy as defined as muscle weakness. Conditions that lead to intrinsic muscle degeneration or restricted skeletal function are not considered by this review. Additionally, while dietary interventions play an important role in these disorders, nutritional management is beyond the scope of this review.
Despite differing physiology across the IEMEM groups, exercise intolerance is common, with clinical features including exercise-induced muscle pain, weakness, fatigue, and rhabdomyolysis. Despite these symptoms, some cohorts can tolerate exercise, and thus we instead propose to use the term 'exercise limitation.' The nature of the exercise limitation is dependent on the type of physical activity undertaken and the energy system involved. 1,2 The three energy systems, adenosine triphosphatephosphocreatine (ATP-PC), anaerobic glycolysis, and oxidative phosphorylation, do not 'switch on' and 'switch off.' They often overlap, with the proportion of ATP produced from each system dependent on the type, duration and intensity of exercise; in addition to the training status of the individual, and any underlying clinical disease or disorder (see Figure 1). 1,2 IEMEM that can affect utilisation of these energy systems include McArdle disease, long-chain fatty acid oxidation disorders (LC-FAOD), and primary mitochondrial myopathies.

| CPET in IEMEM
Over the last two decades, the use of CPET to test exercise capacity in IEMEM has increased. 54 Furthermore, most published studies focus on adult populations, limiting its potential application to children.
McArdle disease appears to be the most common IEMEM condition where CPET has been utilised to assess exercise limitation. Several studies have demonstrated that patients with McArdle disease consistently exhibit a VO 2 peak of 41%-70% of matched controls or normative data (see Table 2). 14,68-76 Furthermore, Munguía-Izquierdo et al. 69 reported 26% of their 81-patient adult cohort did not meet the minimum VO 2 peak threshold level for independent living (13 mL/kg/min). 69 This suggests that patients with McArdle display impaired aerobic fitness; with some patients unable to conduct basic day to day tasks.
CPET can also contribute to the diagnosis of McArdle disease. Eliciting the 'second wind' during steady state submaximal exercise is pathognomonic of McArdle disease. 21,65,77 Studies utilising CPET in adults have repeatedly demonstrated onset of the second wind around the 7th minute of exercise (range 4-15 min), where heart rate (HR), rating of perceived exertion (RPE) and muscle exhaustion decrease. 11,21,65,[78][79][80][81] This second wind is reflective of increased muscle blood flow and oxygen uptake, enabling aerobic glycolysis; as well as mobilisation of alternative substrates including fatty acids and liver glycogen. 77,82 For children with McArdle disease, there are very limited reports regarding the use of CPET. 9,67,74,75 A study of four children undertaking a 15 min steady state treadmill or cycle ergometer CPET reported a reduction in heart rate during the second wind ranging between 6 and 38 bpm; which was less than the 20-69 bpm range reported in adults. 65,67 Although the clinical significance of this difference remains unclear, the authors suggest that the low workload in the paediatric population may have dampened the second wind response. However, it is difficult to draw conclusions from such a small study, and the challenges of eliciting a true maximal exercise test in young subjects may also skew results. 83,84 Given the paucity of existing literature, the optimal CPET protocol for either diagnostic or monitoring purposes for children with McArdle disease has not yet been clearly defined. Similarly, the magnitude of the impairment in VO 2 peak, and the associated exercise limitations F I G U R E 2 Cardiopulmonary exercise testing using a cycle ergometer.
F I G U R E 3 Cardiopulmonary exercise testing data analysis. in children with McArdle disease remain to be fully established.
For patients with LC-FAOD, much of the existing literature on CPET describes single case or small cohort studies designed to assess the efficacy of dietary intervention, such as comparing higher carbohydrate with higher medium chain triglyceride (MCT) diets, or the use of ketones. 42,[85][86][87][88][89][90] In adult patients, there appears to be a trend for lower VO 2 peak compared to control subjects, using cycle ergometry (see Table 3). 66,[91][92][93] Though the available data are quite limited, these findings suggest that patients with LC-FAOD are characterised by impaired aerobic fitness limiting their functional capacity. Additionally, one adult case study with CPTII demonstrated a ventilatory threshold that was 45% of VO 2 peak, lower than quoted comparison norms of 65%-80%. 94 This finding likely reflects the large and early reliance on carbohydrate for both anaerobic and aerobic glycolysis. These LC-FAOD case reports also highlight a trend for elevated RER both at rest and maximal exercise, reflecting a higher carbohydrate reliance, or reduced or absent fat oxidation. 33,66,[91][92][93] These findings were supported by two adult case studies that reported RER values up to 1.18-1.26 at maximal exercise. 42,94 Very few studies have reported the use of CPET in children with LC-FAOD. Two case reports of adolescents found reduced exercise capacity using cycle ergometry; while another reported achieving a cycling power output only 71% of predicted. In these studies, VO 2 data were not reported thus limiting the conclusions that can be drawn regarding aerobic capacity in children with LC-FAOD. [95][96][97] Patients with primary mitochondrial myopathies represent an heterogenous group with a wide spectrum of clinical severity and exercise capacity. An Italian cohort of 1100 predominantly adult patients found that 20.2% of patients experienced exercise limitation, with muscle weakness reported as a common symptom. 98 A recent study reported these patients have a lower ratio of oxygen uptake to power output (work) slope, highlighting a reduced ability to utilise oxygen to attain a particular workload compared to control subjects. 54,56,[99][100][101][102][103] Similar to McArdle disease and LC-FAOD, patients with primary mitochondrial myopathies appear to have significantly lower exercise capacity than their healthy peers, though the evidence in children and adolescents remains quite limited (see Table 4). [99][100][101][102] Within the mitochondrial cohort there is very wide variability in exercise capacity, with some patients not meeting the minimum VO 2 threshold for ADLs (15 mL/ kg/min for women, 18 mL/kg/min for men) 2,104 and others achieving VO 2 peak greater than 90% of predicted. 54,56,105 Investigators suggest this variability is related to the ability of the muscle to extract and utilise oxygen at peak levels of exercise, as well as the mitochondrial mutation load in the muscle, and individual fitness. 54,105 These findings highlight the limited diagnostic value for CPET in patients with primary mitochondrial myopathies due to the phenotypic heterogeneity of the population. 53 This suggests that CPET should be used in conjunction with other diagnostic investigations; or used instead to monitor progress following exercise interventions. Despite these limitations, some variables measured during CPET could be used to establish the suspicion of primary mitochondrial myopathies, although it would warrant further testing. [54][55][56]99,102 The VT occurs earlier and at a lower VO 2 compared to healthy controls, with one study of 17 patients reporting VT occurring at a mean of 46% of predicted VO 2 peak, compared to 65% in the control group. 56 This reflects an earlier and higher reliance on anaerobic glycolysis and carbohydrate as a substrate, which may impact the capacity to sustain exercise at a given intensity. 106 Whether exercise training shifts the VT to a higher percentage of VO 2 peak warrants further investigation.
Similar to LC-FAOD, RER may also be significantly elevated at peak exercise, suggesting higher reliance on carbohydrate and higher lactate production. 1,2,54,55 Taivassalo et al's 54 study on 40 patients reported a mean peak RER of 1.31, compared to controls of 1.14, whilst Heinicke et al. 106 reported a mean peak RER of 1.95 from five patients, significantly higher than controls. However, another study of 13 patients reported similar RER, but significantly lower maximal lactate compared to controls. The authors acknowledged these latter findings were disparate to previous studies, and highlights the heterogenous nature of this cohort. 62,102 Oxygen pulse (VO 2 /HR) at peak exercise can be lower in these patients, indicating higher heart rate, or cardiac demand, is required to achieve the same oxygen uptake as controls; or, that these patients are unable to consume as much oxygen as controls regardless of comparable delivery to the muscle. 56 Two studies have demonstrated that both VE/VO 2 and VE/VCO 2 are both significantly higher in patients with primary mitochondrial myopathies than in healthy controls at both peak exercise and ventilatory threshold, reflecting a hyperventilatory response, potentially to compensate metabolic acidosis. 56,106 Similarly, another study reported peak VE/VO 2 to be significantly higher in the patient group compared to the control group. Conversely, one study demonstrated no difference in VE/VO 2 and VE/VCO 2 at peak exercise compared to controls, although they were both elevated at the VT. 99 The authors suggested that this discrepancy could be due to the inability of the patients to reach their peak ventilation due to premature musculoskeletal limitations.
Healthy populations demonstrate a positive correlation between peak cardiac output and VO 2 peak, indicating that oxygen uptake and utilisation is limited by cardiac capacity, rather than skeletal muscle oxygen extraction; the latter of which is represented by a-vO 2 difference. 54,107 In contrast, one study of patients with primary mitochondrial myopathies found no correlation between peak cardiac output and VO 2 peak, but instead T A B L E 4 Studies investigating exercise limitation in primary mitochondrial myopathies, as defined by VO 2 peak.

Study Population
Mean VO 2 peak (ml/kg/min) demonstrated a positive correlation between a-vO 2 difference and VO 2 peak. 54 This study also reported a significantly reduced peak a-vO 2 difference compared to control subjects. 54 These findings suggest the low VO 2 peak in these patients is likely related to the impaired ability of the muscle to extract and utilise oxygen, presumably due to impairment within the mitochondrial respiratory chain. 54 However, this may be confounded by intrinsic cardiac disease, respiratory insufficiency, and/or neurological compromise, which was not specified in this study. 63,64 One investigation demonstrated a negative correlation between the lactate to VO 2 ratio, and a-vO 2 difference, at peak exercise. 54 This suggests that higher peak exercise lactate in relation to oxygen uptake is associated with higher severity of mitochondrial oxidative deficiency. In this study, the correlation between peak exercise lactate, VO 2 and a-vO 2 difference was not observed in the control group; nor was there a correlation between resting lactate levels and VO 2 peak or a-vO 2 peak in the mitochondrial cohort. While this correlation may be useful in determining disease severity, or primary contributors to exercise limitation, lactate measurement may be impractical outside of CPET.
In addition to the phenotypic variability across and within the IEMEM cohort, clinical population CPET 'normative' values are constrained by methodological inconsistencies across studies, and limited existing data. 2,108-110 Additionally, the risk of inducing rhabdomyolysis may caution against conducting maximal CPET in McArdle disease and LC-FAOD. CPET results can also be affected by familiarisation with equipment and protocols, external motivation, speed of work rate increase, and age of the patient. For the IEMEM population, a conservative approach to CPET protocols should be considered.

| Field tests in IEMEM
Field tests may also prove useful in IEMEM, especially when access to formal exercise testing equipment is limited. Buckley et al. 81 used the 12-min walk test, while monitoring pain, HR, RPE, and walking speed, in adult patients with McArdle disease. They demonstrated a strong and significant correlation between the ratio of muscle pain to walking speed, and heart rate to walking speed. That is, the pain ratings for a specific walking speed were positively correlated with the heart rate for the same walking speed, at most time points. The highest elevations in each of these ratios correlated with the onset of the second wind. This infers that conducting a field walking test with HR, pain, and RPE monitoring could be useful in diagnosis of suspected McArdle disease by eliciting the second wind, as well as prescription of safe physical activity based on pain rating scales. Additionally, distance completed over the 12 min could be utilised to monitor and evaluate exercise intervention therapies.
For one patient with undiagnosed mitochondrial disease, measuring heart rate on a routine walk to school demonstrated tachycardia, with heart rate at 170-190 bpm for most of the 20 min. 103,111 The same patient underwent CPET, with output values depicted in Table 5. The CPET results for this patient were indicative of high cardiac demand to deliver O 2 , and a hyperventilatory response, possibly compensating for low mitochondrial oxidative capacity. Ultimately, this exercise testing led to a provisional diagnosis of mitochondrial disease, later confirmed with muscle biopsy and enzymology. 103,111 Although not routinely used, and with no specific guidelines available for these cohorts, field walking tests may be helpful to diagnose and monitor exercise interventions in IEMEM, especially if CPET equipment or protocols are not available to practitioners.

| PHYSICAL ACTIVITY AND EXERCISE IN IEMEM
A few studies have explored the relationship between daily physical activity levels, and impact on exercise capacity in IEMEM. 11,112 In adult patients with McArdle disease, the intensity of exercise that provokes the second wind appears to be influenced by an individual's daily physical activity and fitness level. Lucia et al. 11 categorised 63 patients as active or non-active based on interviews about their usual physical activity habits. The active cohort (n = 21) reported doing physical activity such as walking, cycling, or swimming, for at least 30 min a day, for five or more days per week. This cohort demonstrated a 23% higher T A B L E 5 CPET data from a paediatric patient with undiagnosed mitochondrial disease. 103 Aerobic "" VO 2 peak* "" peak work* "" VT* 107 McArdle Adult n = 8 Aerobic " VO 2 peak* "" peak work* " Qpeak* 117 McArdle Adult n = 7 Aerobic " VO 2 peak* "" peak work* " Qpeak 116 McArdle Adult n = 10 Control n = 7 Aerobic, RT "" VO 2 peak* # clinical severity score* "" peak work* Aerobic, RT "" VO 2 peak "" peak power 86 LC-FAOD (CPTII) Paed n = 1 Aerobic, RT " VO 2 peak " VT " peak power 117 MM Adult n = 6 Aerobic "" VO 2 peak* "" peak work* "" Qpeak* 125 MM Adult n = 18 RCT Aerobic, RT "" VO 2 peak* " power output " endurance* "" muscular strength* # clinical severity score 101 MM Adult n = 10 Control n = 10 Aerobic " VO 2 peak* " power output* "" VT 113 MM Adult n = 8 Aerobic " VO 2 peak* "" power output* " a-vO 2 peak* VO 2 peak, and a significantly higher proportion of patients in the lowest clinical phenotype severity scores, compared to the inactive cohort. Salazar-Martinez et al. 112 similarly described a cohort of 54 adult patients, categorising 20 of those as active. Inactive individuals experienced the need to rest or stop their physical activity during walking or brisk walking; while 'active' patients only reported the second wind during more strenuous activities including jogging and cycling. Furthermore, during formal exercise testing in this study, the 'active' individuals experienced the second wind at a significantly higher absolute workload and relative VO 2 compared to the 'inactive' patients. This implies that less active patients experience myopathic symptoms at lower intensity activity, impacting an individual's ability to complete normal daily activities without impediment. For more sedentary patients with IEMEM, the limitations to ADLs may increase the risk of further deconditioning with the natural desire to avoid muscular pain and weakness, potentially reducing quality of life. 16,113,114 These findings encourage regular physical activity for patients with McArdle disease, to enable participation in both structured and unstructured activity. However, due to the large heterogeneity in clinical presentation and exercise capacity, interventions should be individually tailored to reduce the risk of myopathic impairment.

| EXERCISE INTERVENTIONS IN IEMEM
Structured exercise interventions for adults with McArdle disease have consistently demonstrated a positive effect on exercise capacity. 82 Multiple small prospective cohort studies have reported improvements in VO 2 peak, work capacity, cardiac output, muscle strength, and clinical severity score after implementation of an aerobic and/or resistance training (RT) program. 68,107,[115][116][117] (See Table 6). Despite these improvements, VO 2 peak in these cohorts remained well below normative data or control groups. 68,107,116,117 However, the VO 2 peak improvement remains clinically significant for this population, reflected by reduced disease severity scores and impairment to ADLs. 68,107,[114][115][116][117][118][119] Although there appears to be a clear and safe benefit of regular exercise in the adult McArdle cohort; this is yet to be determined in the paediatric population. There are very few studies reporting on exercise interventions for children with McArdle disease (see Table 6). 120,121 Conducting such studies may be limited due to common misdiagnosis or under-diagnosis in this age-group; limited access to exercise testing equipment; or concerns about safety or capability of exercise testing in younger age groups. 11,63,121 Only two case studies, one adult, one paediatric, have reported on exercise interventions in LC-FAOD, limiting our capacity to conclude on the efficacy of exercise (see Table 6). 86,122 A similarly limited number of studies regarding exercise interventions can be found in the primary mitochondrial myopathy cohort, though findings from these studies suggest that aerobic training can improve VO 2 peak in adults (see Table 6). 101,113,117,[123][124][125] Similarly to the McArdle cohort, there is wide variability in training program specifications, and measured variables. One randomised controlled trial of 18 patients demonstrated enhanced VO 2 peak, endurance, and muscular strength after a combined 60 min aerobic and RT program on three non- consecutive days per week for 12 weeks. 125 However, it is unclear if these adaptations led to improvements in clinical symptom severity and capacity to perform ADLs. Resistance-only exercise has also been demonstrated to improve muscular strength in adults with primary mitochondrial myopathies, with a trend for improved peak oxygen uptake. 126 However, further research is needed in this area as there is currently only one study exploring RT in adults, and none in children. Schreuder et al. 127 reported on five children with primary mitochondrial myopathies who engaged in regular unsupervised exercise over a period of 18 months. Only one child demonstrated adequate adherence of more than one structured aerobic training session per week, but showed no significant improvement in aerobic capacity. Therefore, conclusions cannot be drawn on the safety or efficacy of structured exercise for paediatric patients with primary mitochondrial myopathies.
Within each of these cohorts, there is clearly wide variability in both exercise capacity, and the extent to which exercise adaptation occurs. Some of this variability may be attributed to the spectrum of disease severity, or interruptions to exercise routine by hospital admissions or associated clinical complications. Training program parameters such as type and frequency of exercise will also affect adaptation. Other mechanisms impacting exercise adaptation may parallel those found in healthy populations. 1

| POTENTIAL MECHANISMS SUPPORTING EXERCISE ADAPTATIONS IN IEMEM
Physiological factors involved in exercise adaptation in healthy populations can be generally grouped into pulmonary, cardiovascular, muscular, and mitochondrial. 1 These adaptations are experienced by deconditioned or sedentary healthy people, and are also likely contributors to the improvement in exercise capacity for patients with IEMEM. Pulmonary adaptations include enhanced ability to extract oxygen from ambient air and improved ventilatory muscle endurance. 1 Similarly, cardiovascular adaptations include increased stroke volume, reduced heart rate for the same workload, increased heart rate at maximal workload, and increased heart mass and volume; overall resulting in improved cardiac output and efficiency. Increased capillary density to the muscle and therefore increased blood flow contribute to improve oxygen delivery, while muscle fibre hypertrophy improves muscular endurance. Increased mitochondrial density in skeletal muscles and increased enzymatic activity contribute to improved oxidative capacity. 1 Furthermore, genetic predisposition to aerobic and strength capacity plays a large role in adaptation to training, as does the training status of an individual. 1 'Untrained' individuals typically experience larger fitness gains in a shorter time period compared to trained individuals.
While some of these 'healthy population' adaptations to exercise are likely relevant in the IEMEM cohort, other theories have been postulated to describe the improvement to exercise capacity in patients with IEMEM.
There are limited cohort studies investigating the mechanism of improved exercise capacity in McArdle disease. Haller et al. 107 linked improved mean peak cardiac output and skeletal muscle mitochondrial enzyme levels to improvements in aerobic fitness following aerobic training. Porcelli et al. 117 reported improved peak cardiac output, stroke volume, and muscle fractional oxygen extraction, resulting in significantly increased VO 2 peak. In healthy populations, aerobic exercise training enhances lipid oxidation at submaximal efforts, which has also been proposed as an adaptive mechanism in McArdle disease. 1,82,128 This has not yet been formally evaluated, though measurement of plasma free fatty acids and ketones; or breath analysis in conjunction with labelled palmitate, pre and post a structured exercise training regimen could provide further insights. Muscular hypertrophy has been demonstrated by Santalla et al.'s 115 adult cohort, with a significant increase to total and lower lean body mass, as well as muscle strength, with resistance training. Increased patient education and awareness of the second wind may be considered an adaptive mechanism, as this allows patients to exercise for longer, which is likely to reduce deconditioning. 77,82 For patients with LC-FAOD, no studies have formally investigated mechanisms of exercise training adaptation. The two existing case reports speculate both muscular and cardiovascular adaptations contributed to improved patient exercise capacity. 86,122 Further research would help to better define the exercise adaptation mechanisms in the context of LC-FAOD.
Several small studies have explored the mechanisms supporting the improved exercise capacity in patients with primary mitochondrial myopathies. Two investigations suggest a 'gene shifting' effect whereby resistance training stimulates the integration of healthy wild-type DNA satellite cells into existing muscle tissue, increasing the proportion of healthy to mutant cells, thereby increasing mitochondrial and oxidative capacity. 126,129 Siciliano et al. 130 demonstrated a significant reduction in mean peak lactate after exercise training, potentially reflecting improved oxidative phosphorylation, lactate recycling, and/or enhanced buffering of lactic acid. Bates et al. 101 further demonstrated similar improvements in cardiac mass, work capacity, VO 2 peak, and VT in patients with primary mitochondrial myopathies compared to sedentary healthy controls.

| EXERCISE PRESCRIPTION IN IEMEM
Recent clinical practice guidelines recommend individuals with McArdle disease undertake both aerobic and strength training to improve cardiorespiratory fitness, increase muscle mass, and reduce disease severity and morbidity. 77 However, these guidelines do not address the need for specific recommendations in adult versus paediatric patients. A review of the literature has highlighted strategies to guide recommendations in these cohorts to encourage safe physical activity. 82 It is suggested to avoid exercise that is reliant on anaerobic glycolysis, including isometric strength movements (such as a plank), and high intensity dynamic exercise, like plyometric or high intensity interval training (HIIT). Being aware of, and utilising the second wind phenomenon could also be key in managing exercise limitations in patients with McArdle disease. A low intensity warm-up for 10-15 min, targeting the active muscles, can enable patients to progress to extended duration exercise of 30-60 min at a low to moderate intensity, multiple times a week. 77,116 For resistance training, a similar warm-up period followed by low repetition sets with adequate recovery times is suggested, to allow replenishment of ATP via the PC energy system. 77,115,116,118,121 It is important to maintain intensity in a range where aerobic glycolysis is the major source of ATP generation, in order to avoid exercise-induced rhabdomyolysis.
There are no robust studies to guide exercise prescription for patients with LC-FAOD, nor any that report on long term outcomes, including safety and efficacy, of exercise programs. 86,122 The consensus management guidelines for VLCADD encourage regular physical activity incorporating both aerobic and strength-based exercise, with adjustments to duration and intensity according to patient tolerance and clinical symptoms. 131 As these patients still have intact anaerobic and aerobic glycolytic pathways, an exercise program of low, moderate, or supervised high intensity exercise could be safe and effective, if adequate carbohydrate and/or mediumchain-triglyceride substrate is provided. 122,131 Similarly, strength-based training could also be undertaken.
For patients with primary mitochondrial myopathies, consensus management guidelines encourage aerobic and resistance training to improve the ability to perform ADLs. 132 However, no specific recommendations have been developed for this group, likely due to the limited evidence available, with only one RCT in adults from which exercise guidelines can be drawn. 125 This RCT demonstrated a combined aerobic and resistance training program of 60 min, three times a week, was safe and effective. Recommendations regarding resistance training suggest the use of high repetitions at low to medium concentric and eccentric loads; while aerobic training should be performed at moderate intensity.
It is important to consider that any exercise which exceeds an individual's capacity with regards to intensity, duration, frequency, or rest periods, may lead to severe rhabdomyolysis in McArdle or LC-FAOD patients; or excessive cardiorespiratory demands in mitochondrial patients. It is thus critical that exercise prescription is personalised to the patient's baseline capacity and particular clinical constraints, introduced gradually, and supervised and modified on an ongoing basis.

| CONCLUSION
Exercise testing has a role in diagnosis and monitoring of inborn errors of muscle energy metabolism. Certain hallmark parameters such as reduced VO 2 peak, reduced ventilatory threshold, elevated RER, reduced oxygen pulse, and/or presence of a second wind phenomenon can be indicative of altered physiology. Standard CPET exercise testing protocols can be reliably utilised to determine changes to exercise capacity. Patients with IEMEM can experience significant and clinically relevant improvements in aerobic and muscle capacity following structured and personalised exercise training. Despite the clear limitations affecting the quality of evidence available to guide exercise prescription in these cohorts, exercise programming in adults with McArdle disease and primary mitochondrial myopathies appears to be safe, effective, and can significantly improve the capacity to undertake basic activities required for independent living. When applying these broad exercise recommendations to paediatric populations, they should be individualised, with consideration to appropriateness and ability to follow structured programs, whilst maintaining patient enjoyment and engagement.
Further investigations are warranted to elucidate the mechanisms behind improved exercise capacity, as well as the interaction between exercise and substrate utilisation. Additional studies need to be undertaken in patients with LC-FAOD, and in children, to better evaluate the safety, efficacy and compliance, especially in the longterm. Multi-centric robust studies will be helpful in providing further insights.

AUTHOR CONTRIBUTIONS
Carolyn Broderick conceptualised the review, Kiera Batten drafted the review; all authors reviewed, provided feedback, and approved the final version.