Ubiquitin-proteasome pathway activation in the diaphragm of humans with reflux esophagitis

Some forms of gastroesophageal reflux disease (GERD) are associated with crural diaphragm (CD) dysfunction, suggesting that GERD may be influenced by skeletal muscle deficiencies. Skeletal muscle atrophy has been strongly linked to alterations in the ubiquitin-proteasome system, the primary pathway for protein degradation. This study aimed to assess the expression of muscle atrophy-related proteins in the CD of patients with reflux esophagitis compared with those without esophagitis. In addition, we examined the correlation between these proteins, esophagitis severity, and esophageal acid exposure. CD biopsies were obtained from 15 volunteers (8 males, 7 females; mean age 43 yr) during antireflux laparoscopic Nissen fundoplication (GERD group) or gallbladder surgery (control group). The GERD group was further classified based on the Los Angeles classification into <i>grades A</i> (<i>n</i> = 5), <i>B</i> (<i>n</i> = 7), and <i>C</i> (<i>n</i> = 3). We analyzed key signaling pathways involved in muscle atrophy, including AKT, phosphorylated AKT (pAKT), muscle-specific RING finger 1 protein (MuRF-1), and muscle atrophy F-box (MAFbx/atrogin-1), normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). No significant differences were observed in MuRF-1, pAKT/AKT ratio, or MAFbx/atrogin-1 expression between the control and GERD groups. However, MuRF-1 expression was significantly elevated in the GERD C group compared with GERD B group. The control group showed no differences from GERD A or B. Notably, MuRF-1 expression correlated with esophageal total reflux time in the supine position. These findings suggest that increased MuRF-1 expression may contribute to CD fiber atrophy and weakness in patients with GERD, potentially impairing gastroesophageal junction function and influencing disease progression.<b>NEW & NOTEWORTHY</b> This study demonstrated, for the first time, an increased activation of the ubiquitin-proteasome pathway and elevated MuRF-1 expression in the crural diaphragm of humans with moderate reflux esophagitis. It showed a positive correlation between the supine reflux time and MuRF-1 expression, suggesting a molecular mechanism associated with diaphragm fiber atrophy and weakness. These findings highlight a potential link between diaphragm degradation and reflux esophagitis, which may modulate gastroesophageal reflux and symptoms.