What role does the Notch signaling pathway play in exercise-related metabolic and neurological adaptations? A molecular-to-systems perspective.

The Notch signaling pathway is a highly conserved cell-cell communication system that plays central roles in stem-cell maintenance, tissue homeostasis, cell-fate determination, and metabolic regulation. Because exercise induces coordinated adaptations across the nervous, muscular, cardiovascular, and metabolic systems, Notch signaling has emerged as a potential mediator of exercise-associated plasticity. However, whether exercise directly activates or suppresses Notch signaling in a causal, tissue-specific, and intensity-dependent manner remains unresolved. In this narrative review, we synthesize evidence on canonical and non-canonical Notch signaling, its functions in neural and metabolic regulation, and its potential intersections with exercise-related neurogenesis, muscle remodeling, redox balance, and metabolite signaling. We contend that the current evidence is best understood within a context-dependent framework rather than through a universal model of exercise-induced Notch activation. In particular, categories such as "moderate" and "high-intensity" exercise should be interpreted as individualized physiological domains defined relative to markers including lactate and ventilatory thresholds, cardiorespiratory reserve, and baseline fitness. We further propose that exercise-derived metabolites, including lactate, ketone bodies, and shifts in cellular NAD+/AMP status, may modulate Notch-related signaling indirectly or in a cell-type-specific manner; however, these interactions should currently be regarded as hypothesis-generating rather than established linear pathways. Across tissues, the strongest mechanistic evidence pertains to Notch biology in neural stem cells, synaptic plasticity-associated signaling, and skeletal-muscle stem-cell regulation, whereas direct human exercise studies assessing Notch pathway activation remain scarce. We therefore propose a context-dependent working model in which Notch acts as a potential integrator of exercise-responsive neural and metabolic cues, while also emphasizing major limitations, conflicting findings, and the safety concerns associated with systemic pharmacological modulation of this pathway. Overall, this perspective positions Notch signaling as a plausible, though not yet universally validated, component of exercise-associated adaptation and a priority target for future mechanistic investigation.