Cystic fibrosis (CF) is an inherited condition resulting from defects in the cystic fibrosis transmembrane conductance receptor (CFTR), which leads to bronchiectasis, chronic airways infection, pancreatic insufficiency, and impaired nutritional status, among other complications. Historically, CF has been associated with significant morbidity, progressive decline in lung function, and early mortality. Unsurprisingly, exercise limitation has also been a common finding in both adults and children with CF [1,2]. There has been a debate as to whether the exercise limitation in CF is because of the impaired cardiorespiratory system's ability to meet metabolic demands or because of CFTR-related intrinsic abnormalities in the muscle itself [3–6]. A common method to measure exercise capacity is through cardiopulmonary exercise testing (CPET), providing multiple measures with the most commonly considered being oxygen consumption (VO2). Others have used functional tests such as the 1-minute sit-to-stand test, the stair climb test, and the 10meter walk test [7,8]. CPET has been recommended in people with CF (pwCF), especially in those with advanced lung disease, as defined as an FEV1 less than 40% of predicted, because the peak VO2 has been associated with survival [1,9,10].

CFTR modulator therapy, especially elexacaftor–tezacaftor–ivacaftor (ETI), has transformed the lives of pwCF, such that people are living longer and experiencing fewer disease-related complications. Although the impact of ETI on improved lung function and reduced pulmonary exacerbations has been well-described, there are disparate reports of the impact of CFTR modulators on exercise capacity. Although a positive benefit has been shown in one study, which included both adults and children with CF [11], another demonstrated no significant effect [12], but both of these studies were in pwCF on a less potent CFTR modulator combination. In this issue, Pérez-Ruiz and colleagues report their evaluation of the impact of ETI on aerobic exercise capacity in children with CF aged 6–11 years [13]. As expected, there was significant improvement in lung function and symptoms; however, there was no change in any of the exercise parameters measured by CPET. This was not affected by whether the children were modulator-naïve or previously on a less potent CFTR modulator combination.

In general, these are not surprising observations. Although FEV1 in this cohort was not normal at baseline, it was only mildly reduced (z-score −0.34). Yet there was further reduction prior to starting ETI and significant subsequent improvement with ETI (from −0.6 to +0.57), which is consistent with other studies [14]. Cardiorespiratory exercise capacity as measured by VO2 max was normal at baseline and so we might not necessarily expect it to improve further even with the increase in lung function. Despite this, there was improvement in the functional measures of exercise (i.e. the 30-second chair stand test, the stair climb test, and the 10-meter walk test); however, these are tests for which there can be a learning effect. We suspect the learning effect is at play here because these tests were improved from baseline prior to starting ETI, despite further reduction in FEV1.

One might ask what this paper adds since these observations have been seen before. There remains the question as to whether CFTR makes a difference at the muscular level, and if so, could there be improvement in muscular activity with CFTR modulators? After all, CFTR is ubiquitous, and present in myocardial cells, vascular smooth muscle, and skeletal muscle [15]. Indeed, the authors noted that there was an unexpected increase in the ventilatory equivalent (VE/VO2, where VE is minute ventilation) measured at the ventilatory threshold, when the rate of ventilation rise changes to a steeper rate, and hypothesized that this could be because of a peripheral muscle effect. More likely, as they also suggest, this is a mere unfortunate finding related to measurement and the small numbers of subjects as the differences are small and not significant. Otherwise, there is no biologic explanation as to why there was an increase in the subjects who were CFTR modulator treatment naïve but not in those previously treated with an alternative CFTR modulator.

This does not mean there cannot be some role for CFTR in the skeletal muscle, but its role may be very difficult to elicit. In another study of exercise including cohorts of pwCF, healthy controls, and subjects with primary ciliary dyskinesia, there was a measurable difference in skeletal muscular oxidative function in the pwCF compared to the others, yet the pwCF achieved a similar exercise workload [16], so the difference in muscular oxidative function was not limiting performance.

So, what can we take away from this study? If we are to show that CFTR deficits compromise cardiovascular or muscular function, then perhaps this is best studied in individuals who are seemingly healthier and not always those with more established lung disease. For the latter, it is very difficult to ignore the impact of pulmonary impairment in exercise limitation. In this case, this study showed no meaningful impact of ETI on exercise capacity, and although that does not rule out some improved muscular effect, it is not sufficient to be assessed using testing such as CPET. We can also suggest that there is limited value to routine exercise testing in pwCF despite recommendations [8]. Although exercise testing can identify exercise-related hypoxemia and even offer prognostic information (re: mortality), these are only applicative in subjects who have advanced stage lung disease.