Epidemiologic studies suggest a link between age-related skeletal muscle decline (sarcopenia) and lower urinary tract dysfunction. However, whether skeletal muscle loss directly alters bladder function and the related underlying molecular mechanisms remain unclear. We hypothesized that aging-related skeletal muscle decline induces bladder dysfunction and that shared transcriptional alterations arise in both the skeletal muscle and the bladder. The present study aimed to characterize functional bladder changes and identify common molecular pathways underpinning these changes across both tissues.

Female C57BL mice were used. An aging-related muscle-decline (“older muscle decline”) model was generated by housing 8‑month‑old mice on a 10% glucose solution only for 7 days. The following two control groups were included: age-matched older (8 months) and young (8 weeks) control groups. Under anesthesia, a bladder catheter was placed. Continuous cystometry was then performed under awake, restrained conditions. After cystometry, the gastrocnemius (hindlimb) muscle and bladder were harvested. A portion of the bladder was used for isometric contraction assays, including electrical field stimulation (2, 8, and 32 Hz) and pharmacologic stimulation with carbachol and KCl. Microarray profiling was conducted on the gastrocnemius and bladder tissues. For each tissue, the top 30 differentially expressed genes were extracted, and WikiPathways-based analyses were performed to identify the shared pathways between tissues.

Compared with the age-matched older controls, the older muscle‑decline mice exhibited reduced body and gastrocnemius weights. The bladder weight increased in the older muscle‑decline group relative to both young and older controls. On cystometry, the older muscle‑decline group showed longer intercontraction intervals, greater voided volume and bladder capacity, higher postvoid residual, and more frequent non‑voiding contractions(Figure 1A). In the isometric contraction assays, contractile responses to electrical stimulation (2, 8, and 32 Hz) and pharmacologic stimulation with carbachol and KCl were consistently attenuated in the older muscle‑decline group compared to the young and older controls (Figure 1B). Microarray analyses demonstrated a clear differential expression in both bladder and gastrocnemius tissues of the older muscle‑decline and age‑matched older mice (Figure 2A/B). The upregulated genes in the muscle‑decline group were enriched for Toll‑like receptor signaling, p53 signaling, and mRNA processing, whereas the downregulated genes were enriched for PI3K–Akt–mTOR signaling and striated muscle contraction.

Aging-related skeletal muscle decline is associated with a multifaceted bladder dysfunction—characterized by capacity enlargement, residual urine accumulation, and increased non‑voiding contractions—together with reduced smooth muscle contractility. The concordant transcriptional signature across the skeletal muscle and bladder—marked by inflammatory/stress pathway (Toll‑like receptor signaling; p53 signaling) activation and anabolic/contractile program (PI3K–Akt–mTOR; striated muscle contraction) suppression—supports a shared pathophysiologic axis connecting systemic muscle decline to bladder dysfunction.

Older mice with skeletal muscle decline exhibited bladder enlargement, impaired voiding efficiency, and diminished contractile function. Shared molecular alterations, characterized by upregulated inflammatory/stress signaling and downregulated anabolic/contractile pathways, likely contribute to this phenotype. These findings suggest sarcopenia‑related muscle decline as a driver of bladder dysfunction and highlight common molecular pathways as potential therapeutic targets for lower urinary tract dysfunction in the context of aging.