NE06 Molecular mechanisms of persistent endocrine myopathy: beyond biochemical remission

Abstract

Impaired muscle quality in patients with Cushing's syndrome (CS) and Acromegaly (ACRO) is associated with persistent muscle weakness, altered physical function, and reduced quality of life (QoL), even after long-term biochemical control. The mechanisms underlying sustained myopathy remain unclear. We hypothesized that skeletal muscle retains a lasting molecular memory of prior hormonal excess. We performed a multi-omic analysis of rectus femoris muscle samples from hormonally controlled patients with CS (n=6) and ACRO (n=7), all in remission for at least 5 years. Mass spectrometry-based proteomics and phosphoproteomics were integrated with DNA methylation profiling. Both diseases displayed homogeneous and distinct proteomic signatures. ACRO samples showed 328 differentially expressed (DE) proteins and 1,111 phosphopeptides, consistent with metabolic reprogramming toward glycolysis, structural remodeling associated with hypertrophy, and impaired calcium handling. CS samples exhibited 274 DE proteins and 118 phosphopeptides, reflecting a catabolic phenotype characterized by activation of the ubiquitin–proteasome system and oxidative stress pathways. Comparative analysis revealed a convergent reduction in muscle plasticity, with nearly 50% of DE proteins shared between conditions and enriched in pathways related to metabolic stress adaptation and protein quality control. Both diseases also exhibited selective hypophosphorylation of histone H1.4 and coordinated DNA methylation changes at HOX loci on chromosomes 7 and 12. These findings support the existence of a persistent molecular footprint in skeletal muscle after biochemical remission. A shared epigenetic memory of prior GH or cortisol excess may contribute to long-term muscle dysfunction and represents a potential target for therapeutic intervention.