Hormonal dimorphism in sarcopenia disease

Sarcopenia, affecting over 60% of individuals above age 80, represents a critical challenge for aging populations worldwide. Despite formal recognition as a disease by the WHO in 2016, therapeutic approaches remain limited to exercise and nutritional interventions, with no approved pharmacological treatments. Current management strategies follow a universal paradigm that assumes similar pathophysiological mechanisms across all patients, yet clinical outcomes demonstrate marked variability that may reflect fundamental sex-specific differences in muscle-aging biology. This review interrogates sexual dimorphism in muscle-aging pathophysiology through the lens of three peptide hormones, i.e., apelin, insulin, and oxytocin, and proposes sex-stratified therapeutic strategies. We analyzed pathophysiological mechanisms underlying sarcopenia, focusing on the complex hormonal regulatory network of apelin, insulin, and oxytocin and its effect on satellite-cell dysfunction, proteostasis, stress, and inflammation.

Sarcopenia manifests through fundamentally different pathways in men and women. Women experience precipitous muscle loss during menopause through rapid estrogen decline that disrupts apelin signaling, accelerates insulin resistance, and compromises oxytocin-mediated regeneration. Men demonstrate gradual deterioration paralleling testosterone reduction, with differences among individuals in hormonal dysfunction patterns. Apelin serves as a biomarker primarily in women, while myostatin functions specifically in men. Insulin sensitivity exhibits profound sexual dimorphism, with women maintaining superior muscle glucose metabolism until menopause. Current therapeutic approaches may optimize treatments for one sex while producing suboptimal outcomes for the other. Fewer than 30% of muscle aging studies report sex-disaggregated results, creating critical knowledge gaps. Effective sarcopenia management requires a deeper understanding of peptide-hormone deregulation and development of biologically informed therapeutic strategies that acknowledge distinct disease mechanisms in men and women.