Muscle: A Pivotal Player in Systemic Disease, a call for Clinical Research

Abstract

Metabolic and neurodegenerative conditions pose a significant global health cha-llenge, necessitating innovative strategies that address underlying mechanisms rather than merely managing symptoms. Emerging research highlights skeletal muscle as a central regulator of systemic metabolism and inter-organ communication, mediated by its secretome, epigenetic plasticity, and structural integrity. The muscle secretome, a complex array of signaling proteins, influences lipid and glucose metabolism, tis-sue remodeling, and neuroprotective pathways, thereby offering new avenues for bio-marker discovery and therapeutic intervention. Epigenetic regulation—encompassing DNA methylation, histone modifications, and miRNA expression—mediates exercise-induced transcriptional adaptations that enhance mitochondrial biogenesis, metabolic flexibility, and inflammatory control. Conversely, muscle atrophy disrupts these adap-tive processes, contributing to insulin resistance, chronic inflammation, and neurode-generation through altered proteostasis and mitochondrial dysfunction. These inter-connected mechanisms underscore skeletal muscle’s pivotal role in maintaining syste-mic homeostasis. Interventions such as exercise training, nutritional modulation, and pharmacological targeting of myokines or epigenetic enzymes show promise for per-sonalized therapies. Future research should prioritize integrative approaches that exa-mine the crosstalk between muscle-derived factors, metabolic regulation, and neuro-plasticity. Understanding how the muscle secretome and its epigenetic regulation in-teract to prevent atrophy and promote resilience could transform the management of metabolic and neurodegenerative disorders, paving the way for precision medicine.