Abstract
Anorexia nervosa (AN) is a severe psychiatric disorder characterized by prolonged caloric restriction and significant weight loss, including loss of skeletal muscle. However, physiological changes during AN and following weight restoration are poorly understood, especially skeletal muscle physiology and how it relates to systemic physiology. In this study, we utilized a rodent model of AN and weight gain to investigate proteomic changes across the skeletal muscle and serum and how these proteomic alterations relate to muscle functional outcomes. Using SOMAscan proteomics, we identified extensive alterations in the skeletal muscle proteome during 30 days of simulated AN, with the majority of these changes persisting after weight restoration. Muscle mass and strength were not fully recovered after weight restoration, aligning with sustained dysregulation of proteins related to apoptosis, calcium handling, and satellite cell proliferation in skeletal muscle. By contrast, serum proteomic changes were modest during AN but markedly altered and largely distinct from muscle during recovery. TRAIL (TNF-related apoptosis-inducing ligand) emerged as a potential non-invasive biomarker of muscle health as TRAIL content correlated between muscle and serum as well as muscle functional assessments. Proteomic biomarkers of muscle versus systemic AN are largely unique, underlining the complexity of this illness and the need for novel analytical approaches; however, TRAIL dysregulation may be a conserved feature across tissues and should be further investigated as potential non-invasive biomarker of muscle health and a possible mechanistic target for AN-induced muscle loss.