Growth hormone causes reversible fibrosis in muscle and fat: a study in patients with acromegaly

BACKGROUND: Adipose tissue (AT) fibrosis impairs tissue function and is linked to obesity and insulin resistance. Acromegaly, caused by growth hormone excess, promotes lipolysis-driven insulin resistance and profound stimulation of collagen synthesis. It is unknown if this translates into excessive tissue fibrosis. AIM: Quantification of collagen turnover and fibrosis in fat and muscle in patients with acromegaly before and after treatment. METHODS: Two patient cohorts were examined before and after treatment. In cohort 1 (n = 17), AT collagen content and fibrosis- and inflammation-related gene expression were analyzed. In cohort 2 (n = 15), skeletal muscle collagen content, and serum fibroblast activation protein (FAPα) activity and levels were analyzed. Collagen turnover serum biomarkers were analyzed in both cohorts. RESULTS: AT collagen content (%) decreased from 4.6 ± 2.9 before to 2.1 ± 1.2 after disease control (P < .05). AT type I and III collagen gene expression decreased by 53% and 39%, respectively, and correlated closely with disease activity. Muscle collagen content (relative units) decreased from 0.020 ± 0.004 to 0.012 ± 0.008 after disease control (P = .0460). FAPα activity (RFU/min) and levels (µg/L) decreased following disease control (373 ± 111 [before] vs 248 ± 62 [after]; P < .0001, and 102 ± 35 [before] vs 63 ± 23 [after]; P < .001, respectively). In both cohorts, collagen turnover biomarkers declined after disease control. Inflammatory markers were unaffected. CONCLUSION: Our study reports for the first time that prolonged growth hormone excess induces reversible fibrosis in human adipose and muscle tissue. We hypothesize that fibrosis in acromegaly is mainly driven by a direct effect on collagen formation and likely not secondary to inflammation, which contrasts with obesity-driven AT fibrosis. CLINICAL TRIAL REGISTRATION NUMBER: NCT00647179; NCT03431727.