Effect of Growth Hormone on Branched-Chain Amino Acids Catabolism in Males With Hypopituitarism

Abstract

To investigate the impact of growth hormone (GH) on branched-chain amino acids (BCAAs) catabolism in males with hypopituitarism, we measured the concentration of amino acids in 133 males with hypopituitarism and 90 age-matched healthy controls using untargeted metabolome. A rat model of hypopituitarism was established through hypophysectomy, followed by recombinant human GH (rhGH) intervention. Targeted metabolomics and label-free quantitative phosphoproteomics were utilised to assess amino acid levels in rats and explore the mechanisms of GH's effect on BCAA catabolism. Hypopituitarism exhibited elevated concentrations of BCAAs, which correlated positively with triglyceride, fasting insulin and HOMA-IR. The BCAAs were significantly elevated following hypophysectomy and were substantially reduced upon rhGH intervention. Phosphorylation proteomics analysis in liver tissues revealed that differentially expressed phosphoproteins (DEPPs) after GH treatment were predominantly involved in ‘RNA metabolic process’, ‘Diseases of signal transduction by growth factor receptors’ and ‘BCAAs degradation’. Notably, 12 proteins in the BCAA degradation pathway showed altered phosphorylation without whole protein changes. Importantly, the expression or phosphorylation modification of BCKDH, BCATs and MuRF1 were restored through rhGH intervention. Hypopituitarism exhibits elevated levels of circulating BCAAs. The increased circulating BCAAs in hypopituitarism may result from enhanced MuRF1-mediated muscle proteolysis, which greatly exceeds the BCAA degradation capacity. This study provides valuable insights into the effects of GH on BCAA catabolism at the scale of the proteomics level.