Background: People with cystic fibrosis (pwCF) often have multifactorial peripheral muscle abnormalities attributed to, for example, malnutrition, steroid use, altered redox balance and, potentially, CF-specific intrinsic alterations. Malnutrition in CF now includes an increasing prevalence of overweight and obesity, particularly in those treated with CF transmembrane conductance regulator (CFTR) modulators. We aimed to characterise peripheral muscle function and body composition of pwCF on Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTR modulator treatment, compared to healthy controls. Methods: Fifteen pwCF on ETI, and 15 healthy age- and sex-matched controls (CON), underwent whole-body dual-energy X-ray absorptiometry scans, and a comprehensive evaluation of peripheral muscle function. These tests included quadriceps maximal isometric force measurement, an intermittent isometric quadriceps fatiguing protocol, handgrip strength dynamometry, squat jump height assessment, and a 1-minute sit-to-stand test. Results: No differences in quadriceps maximal isometric force (CON: 181.60 ± 92.90 Nm vs. CF: 146.15 ± 52.48 Nm, P = 0.21, d = 0.47), handgrip strength (CON: 34 ± 15 kg vs. CF: 31 ± 11 kg, P = 0.62, d = 0.18), peripheral muscle endurance, fatigue, or power were observed between the groups ( P>0.05). Moreover, no differences in whole-body, trunk or limb lean mass, fat-free mass, fat mass, or whole-body bone mineral density were evident ( P>0.05). Conclusion: Comparable peripheral muscle mass and function may be achievable in pwCF on ETI, especially those with good lung function. Research is needed to confirm these improvements in pwCF who have more severe lung disease, are less physically active, and have less optimal nutrition and exercise support.

This study investigated whether Elexacaftor-Tezacaftor-Ivacaftor (Kaftrio ®), a cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator, could improve exercise capacity in adolescents with CF. After six weeks treatment, Kaftrio ® improved both maximal and submaximal indices of aerobic fitness. Improvements were independent of changes in ventilatory function during exercise and physical activity. Interestingly, pulmonary oxygen uptake per unit of power output was higher in two, out of three, cases who presented with more severe CF lung disease. These findings suggest improved O 2 extraction and/or consumption in the exercising muscle and demonstrate, for the first time, that short-term treatment with Kaftrio ® might improve aerobic fitness in people with CF, especially in those with more severe lung disease and deconditioning.