Abstract
Growth failure in cystic fibrosis (CF) patients has been well-documented and shown to correlate with poorer disease outcomes. This observation is also true in CF animal models, including mouse, pig, rat, and ferret. The etiology underlying growth deficits is unknown, and our previous work demonstrated reduced tubulin acetylation in CF cell models and tissue that is correctable by inhibition of histone deacetylase-6 (HDAC6). Here, we hypothesize that loss of HDAC6 will improve growth phenotype in a CF mouse model. Hdac6 knockout mice were crossed with F508del (CF) mice to generate F508del/Hdac6 (CF/HDA) mice. Growth, fat deposits, survival, and bioelectric measurements were analyzed. CF/HDA mice displayed improvements in length and weight with no correction of CFTR function. Mechanistically, Igf1 levels likely account for increased length and improvements in fertility. Weight gain is attributed to increased fat deposits potentially mediated by increased adipocyte differentiation. CF-related growth deficits can be improved via inhibition of HDAC6, further implicating it as a potential therapeutic target for CF.
Highlights
Given the potential clinical importance of improving growth, growth hormone therapies have been attempted in cystic fibrosis (CF) trials
Reduced ac-tub in CF mouse nasal epithelium is consistent with our previous results, though total tubulin appears to be lower in some CF samples than we found in Cftr-null (S489X/S489X) mice in our previous study[16]
Several studies of growth patterns in CF have demonstrated that CF patients on average are shorter in stature and have less fat deposits than aged matched controls[1, 2]
Summary
Given the potential clinical importance of improving growth, growth hormone therapies have been attempted in CF trials. We have identified that CF cells exhibit significant alterations to microtubule regulation One of those alterations is reduced levels of acetylated tubulin in CF cells compared to non-CF controls. Increased acetylated tubulin of the F508del/Hdac[6] mice did not improve CFTR function as determined by nasal potential differences. Both lengths and weights of F508del/Hdac[6] mice improve to that of wild-type (WT) control. Improvements in lengths can be attributed to increased Igf[1] levels, while increased inguinal fat contribute to improvements in weight This manuscript is the first report of a correction of CF-related growth defects and points to microtubule acetylation as a novel therapeutic target to improve growth in CF patients
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