Developmental programming of skeletal muscle aging by parental exercise: Intergenerational mechanisms and...

Age-related skeletal muscle decline contributes substantially to loss of physical independence and impaired metabolic health, yet its trajectory varies considerably among individuals. Fundamental determinants of muscle function, including architecture, cellular composition, and metabolic capacity, are established during prenatal and early postnatal development. During these windows, skeletal muscle exhibits substantial plasticity in response to parental physiological and metabolic states, raising the possibility that parental exercise shapes offspring muscle phenotypes and later-life aging trajectories. This critical review examines preclinical evidence linking maternal and paternal exercise to offspring skeletal muscle development and evaluates whether these programmed adaptations may confer resilience to age-related muscle deterioration. Current animal studies suggest that parental exercise induces persistent alterations through distinct intergenerational pathways, including paternal germline transmission mediated by sperm-derived small non-coding RNAs and maternal regulation through placental, metabolic, and endocrine signaling. These pathways may shape myogenic development, mitochondrial function, and metabolic homeostasis in offspring muscle, with effects on biological processes that are also implicated in age-related muscle decline, including muscle mass maintenance, mitochondrial quality control, metabolic flexibility, and regenerative capacity. However, current evidence is largely limited to fetal, juvenile, and metabolically challenged adult offspring, with few studies in naturally aged offspring. Although epigenetic memory has been proposed as a mechanism sustaining developmentally induced adaptations across the lifespan, direct evidence of long-term protection against age-related muscle decline is lacking. Longitudinal studies in naturally aged animal models and human cohorts are needed to determine whether parental exercise-induced developmental programming could promote intergenerational muscle health and extend health span.