Progressive Weighted Wheel Running Enhances Neuromuscular Junction Innervation and Muscle Power in Aged Mice

Aging in humans is accompanied by a substantial 30–40% decline in skeletal muscle mass and function, making sarcopenia a major contributor to frailty and loss of independence. Morphologic alterations at the neuromuscular junction (NMJ) are considered to be major contributors to age‐related muscle weakness and likely indicate motor unit instability. Terminal Schwann cells are essential for NMJ maintenance and repair, yet their role in aging and their plasticity with exercise remains poorly defined. Our prior work has illustrated that Progressive Weighted Wheel Running (PoWeR) supports improvements in muscle fiber size and strength, but it is unknown whether PoWeR can improve NMJ innervation and terminal Schwann cell abundance in aged mice. We hypothesize that PoWeR will elicit adaptive responses that mitigate age-related muscle weakness and NMJ destabilization in aged mice, potentially through enhancement of terminal Schwann cell abundance. Twenty-two-month-old female C57BL/6N mice were randomly assigned to PoWeR or sedentary control as we have previously published. In vivo contractile function of the plantar flexors was assessed in the right hind limb, after which muscles were harvested for immunohistochemical analysis. Soleus and gastrocnemius muscles were processed for immunofluorescent detection of terminal Schwann cells and NMJ morphology. Additionally, RNA-seq analysis was performed on the soleus with a curated analysis of genes that support the NMJ. PoWeR training significantly improved pre- and postsynaptic alignment in the soleus (Control: 56±11%; PoWeR: 81±20%) and modestly increased endplate area (Control: 2562±822 µm 2 ; PoWeR: 2865±537 µm 2 ). NMJ fragmentation was reduced (Control: 2.2±0.4; PoWeR: 1.5±0.4), and terminal Schwann cell number per NMJ increased (Control: 1.9±0.8; PoWeR: 3.7±1.6). We observed increased expression of genes associated with NMJ-stability in the soleus as well. PoWeR-trained mice showed elevated rate of torque development and lower time to peak torque compared to controls (p< 0.05). No significant changes were detected in the gastrocnemius. Collectively, these adaptations indicate that PoWeR training improves indices of muscle power, enhances NMJ structural integrity, and supports elevated terminal Schwann cell abundances in aged soleus muscle. The lack of comparable effects in the gastrocnemius suggests muscle-specific responsiveness, perhaps influenced by fiber type and loading patterns. These findings suggest that appropriately designed exercise paradigms may counteract aging-induced neuromuscular decline. This work was supported by NIH awards R01AR072061 and R01AR083375. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.