A comprehensive model for the converging biologies that underpin the homeostatic sleep signal

Sleep has long been understood as a process regulated primarily by central mechanisms, including homeostatic pressure and circadian rhythms. However, emerging research reveals that skeletal muscle actively participates in sleep regulation, functioning as an endocrine organ that releases bioactive molecules capable of influencing brain function. This review examines the growing body of evidence supporting a muscle-derived contribution to sleep homeostasis, focusing on key signaling molecules such as interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), irisin, lactate, and methylglyoxal. We explore their molecular pathways, receptor interactions, and integration with well-established central regulators of sleep, including adenosine and cytokine signaling networks. Compelling genetic evidence, particularly from studies manipulating Bmal1 expression specifically in muscle, demonstrates that peripheral tissues can modulate sleep depth and recovery independently of the brain's central mechanisms. These findings support the idea that skeletal muscle functions as a systemic sensor of fatigue, relaying metabolic and inflammatory cues to the brain that help calibrate sleep need. Recognizing this muscle-brain crosstalk opens new directions for translational research, including exercise-based therapies and pharmacological strategies targeting myokine pathways to enhance sleep quality. This evolving perspective challenges the traditional view of sleep as a process governed solely by the brain, positioning skeletal muscle as an active and essential regulator of sleep-wake dynamics.