MON-059 Skeletal Muscle Proteomic Signatures In Controlled Acromegaly Patients Reveal Potential Molecular Mechanisms Of Long-term Muscle Dysfunction

Abstract Disclosure: J. Gil: None. L. Martel-Duguech: None. R. Díaz: None. J. Bech: None. C. Nuñez-Peralta: None. E. Gallardo: None. S. Webb: None. E. Valassi: None. Patients with acromegaly often exhibit impaired muscle quality and physical performance, even long-term after control of GH/IGF-I excess. These sustained alterations suggest that molecular changes may occur in the skeletal muscle of acromegaly patients, which are not reversed by hormone normalization. The objective of our study was to analyse the proteomic characteristics of muscle cells obtained from the thighs of patients with controlled acromegaly. We hypothesized that there are specific abnormalities of protein expression in muscle of acromegaly patients, which could be related to the significant deterioration of muscle structure and function which has been recently described in clinical studies. To investigate this, we performed an LC-MS-based proteomic analysis of rectus femoris muscle needle biopsies obtained from 8 biochemically cured male acromegaly patients (mean age ± SD: 50 ± 11 years; BMI: 28.0 ± 1.7 kg/m²; median disease control duration: 112 months [IQR: 88]) and 7 age- and sex-matched healthy controls (age: 50 ± 6 years; BMI: 29.0 ± 2.6 kg/m²). We identified 247 differentially expressed (DE) proteins (FDR < 0.05, |logFC| > 1), including structural and contractile elements like titin, and myosin isoforms, consistent with muscle hypertrophy. PCA and hierarchical clustering clearly separated acromegaly samples from controls. Pathway enrichment analysis (Metascape) revealed dysregulation of processes linked to cytoskeletal and sarcomeric organization, including “actin filament organization” and “sarcomere organization.” A strong cellular stress response was also observed, with enrichment of “protein folding,” “response to heat,” and “chaperone-mediated folding,” pointing to activation of proteostasis mechanisms (e.g., heat shock proteins, ubiquitin-proteasome system). These changes reflect ongoing cellular stress and an effort to maintain muscle integrity. Metabolic reprogramming was also prominent. The gluconeogenesis pathway (FDR < 0.01, FE = 12.1) and the glycolytic process (FDR < 0.01, FE = 11.6) were simultaneously enriched, pointing to potential substrate cycling and a hypermetabolic phenotype. This dual upregulation may reflect inefficient energy use, residual insulin resistance, or an attempt to meet increased energy demands under stress.Protein-protein interaction (PPI) network analyses confirmed the presence of disease-specific molecular modules, revealing a distinctive pathophysiological process of muscle remodeling in acromegaly. These findings provide novel insights into the long-term molecular consequences of prior GH excess. Even after biochemical control, acromegaly is associated with a specific muscle proteomic footprint potentially related to persistent functional deficits. Presentation: Monday, July 14, 2025