Professional · Issue 2 · 2026-09-28
Peripheral Muscle Dysfunction Persists in CF Despite Long-Term Elexacaftor/Tezacaftor/Ivacaftor Therapy
Editorially reviewed research summaries, context, and limitations.
Antoine Bronstein, Elise Zitta, Oussama Saidi et al.
Summary: This controlled cross-sectional study compared peripheral muscle function in 56 adults with cystic fibrosis (95% on elexacaftor/tezacaftor/ivacaftor for a mean of approximately 31 months) against 46 healthy age- and sex-matched controls. People with CF showed statistically and clinically meaningful deficits in quadriceps strength, quadriceps endurance, quadriceps muscle thickness, and handgrip strength. Critically, quadriceps strength remained lower even after normalization to muscle thickness, suggesting impairment beyond simple muscle atrophy or physical inactivity.
Why it matters: The widespread adoption of highly effective CFTR modulator therapy (HEMT) has transformed the disease trajectory for many people with CF, raising a reasonable but important question: have extrapulmonary manifestations such as muscle dysfunction resolved, attenuated, or persisted? This study provides the first relatively large, systematically conducted controlled assessment addressing that question. The finding that intrinsic muscle quality — not merely muscle bulk or sedentary behavior — appears compromised has direct implications for rehabilitation, exercise programming, and long-term disease management, even in an era when lung function is substantially preserved by modulator therapy.
Expert perspective: The study is methodologically careful in several respects. The sample size of 56 CF participants is modest but is described as the largest controlled study of this specific question to date. Measurement of muscle function followed international recommendations, multiple muscle groups were evaluated, and accelerometry was used to objectively quantify physical activity — a meaningful improvement over self-report. Effect sizes (rank-biserial correlations of 0.27–0.47 and Cohen's d of 0.48) are in the small-to-moderate range, indicating real but not dramatic impairments; the clinical framing as "clinically relevant" is reasonable rather than hyperbolic.
However, several limitations deserve attention. The cross-sectional design precludes any causal inference about HEMT's effect on muscle function over time. There is no pre-HEMT baseline for these participants, so it is impossible to determine whether the deficits observed represent residual dysfunction that has improved from a worse pre-modulator state, or dysfunction that has been entirely unresponsive to HEMT. The mean FEV₁ of 77% predicted indicates a relatively well-preserved lung function cohort, which may limit generalizability to more severely affected individuals. The authors' inference that "intrinsic muscle alterations" are present — based on strength remaining lower after normalization to thickness — is plausible and mechanistically interesting, given that CFTR is expressed in skeletal muscle and mitochondrial dysfunction in CF muscle has been reported, but normalization to ultrasound-measured thickness is an imperfect proxy for true muscle quality, and residual confounding from nutritional adequacy, chronic systemic inflammation, and prior corticosteroid use cannot be excluded.
The practical message is sound and not overstated: clinicians should not assume that HEMT has resolved muscle dysfunction, and exercise and rehabilitation interventions remain relevant components of comprehensive CF care. For researchers, this study reinforces the need for longitudinal, ideally pre/post modulator studies with detailed muscle phenotyping — including imaging, biopsy, and metabolic testing — to determine whether and how CFTR correction at the molecular level translates to improved muscle biology over time.
Relevance: Cystic Fibrosis
Source: https://pubmed.ncbi.nlm.nih.gov/42674955/
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