Impact of ΔF508 CFTR Mutation on Diaphragm Function During Acute Inflammation

Background: Cystic fibrosis (CF) is caused by CFTR mutations and associated with skeletal muscle dysfunction. Prior work showed exaggerated inflammatory activation of proteolysis pathways in diaphragms of CFTR-null mice. However, effects of the more clinically relevant ΔF508 (DF-CFTR) mutation on diaphragm function are unknown.

Methods: Homozygous DF-CFTR mice (Cftr ^tm1EUR ) and wild-type (WT) littermates received intraperitoneal PBS or LPS (5 mg/kg). After 24 h, we evaluated diaphragm mass and fiber types; expression (mRNA) of cytokines (IL1β, IL6), the unfolded protein response (UPR), and proteolysis (ubiquitin-proteasome, autophagy-lysosome); calpain activity; oxidative stress markers (malondialdehyde, 3-nitrotyrosine); and ex vivo muscle contractility.

Results: Oxidative stress markers were higher in DF-CFTR diaphragms at baseline and in response to LPS. Atrogin1 and autophagy markers (LC3B, Gabarapl1) were more strongly induced by LPS in DF-CFTR. Expression of cytokines, UPR, and other proteolysis pathways (Murf1, calpain) were equivalent. Diaphragm mass, fiber diameter and fiber type proportions did not differ between groups. Contractile function did not differ at baseline, but only DF-CFTR diaphragms showed reduced force production after LPS.

Conclusion: During an acute inflammatory challenge, DF-CFTR diaphragms exhibit exaggerated oxidative stress and proteolysis signalling together with greater force loss. These findings support an increased vulnerability to diaphragm dysfunction linked to the DF-CFTR mutation.