Peripheral muscle dysfunction persists in the era of highly effective CFTR modulators in cystic fibrosis.

Background

Peripheral muscle dysfunction is a well-established extrapulmonary manifestation of cystic fibrosis (CF), contributing to exercise intolerance and reduced quality of life. However, its persistence in the era of highly effective CFTR modulator therapy (HEMT) remains unclear.

Methods

Fifty-six people with CF (age: 31 ± 13 years, BMI: 22 [20-24] kg·m-2; FEV1%: 77 ± 24; 95% treated with elexacaftor/tezacaftor/ivacaftor for 31 ± 11 months) were compared with 46 healthy controls of comparable age and sex distribution. Muscle function was assessed following international recommendations, including quadriceps strength (primary outcome), endurance and thickness, handgrip strength, and squat jump performance. Physical activity was assessed using accelerometry.

Results

Compared with controls, people with CF exhibited lower quadriceps strength (203 [161-304] vs. 284 [238-335] N·m, p = 0.001, rrb = 0.35) and endurance (p < 0.001, rrb = 0.47). Quadriceps thickness (p = 0.002, rrb = 0.34) and handgrip strength (p = 0.009, d = 0.48) were also lower. After normalisation to muscle thickness, quadriceps strength remained lower (p = 0.01, rrb = 0.27), whereas habitual physical activity levels did not differ significantly between groups.

Conclusion

This is the first large controlled study to comprehensively assess peripheral muscle function in people with CF following long-term HEMT exposure. Despite this prolonged exposure, clinically relevant impairments remained evident across multiple dimensions of muscle function. Altered muscle performance cannot be explained solely by muscle deconditioning and lower muscle size, suggesting intrinsic muscle alterations. These findings support the need for comprehensive assessment of peripheral muscle function and the continued prioritisation of interventions aiming to optimise muscle health.