Effects of undercarboxylated osteocalcin on voluntary running and muscle function in aged mice

Introduction: Advancing age is characterized by a gradual deterioration of skeletal muscle mass and function, resulting from impaired anabolic signaling, reduced mechanical loading, and alterations in neuromuscular integrity. Undercarboxylated osteocalcin (unOC), a bone-derived hormone released during bone turnover, has been suggested to improve muscle metabolism and exercise capacity, but its role in aged muscle remains unclear. Physical activity can counteract age-related decline through improved contractile performance and metabolic efficiency. This study investigated whether unOC modulates muscle strength directly or indirectly by influencing voluntary running activity in aged mice. Methods : Male C57BL/6 mice (16 months old) were assigned to four groups (n= 16 per group): Veh+Sed (vehicle, sedentary), Veh+Run (vehicle, voluntary running), OC+Sed (unOC, sedentary), and OC+Run (unOC, voluntary running). Mice were housed individually. Sedentary groups were provided a locked running wheel, whereas running groups had free wheel access. unOC was delivered via subcutaneous osmotic pumps (150 ng/h) implanted at week 0 and replaced at week 4; controls received vehicle (NaCl). Body weight (BW), food intake, and grip strength (GS) were measured weekly. Running distance and maximum velocity were recorded every 24 h. After 8 weeks, body, organ, and muscle weights were measured. Analysis of variance was conducted with OC, Run and time as main effects, and post hoc Tukey test was used to identify group differences. Results : Running distance and velocity increased until day 25 and then declined; neither was influenced by unOC, and interactions with time were not significant. GS was higher in running groups than sedentary groups and increased over time; OC had no effect. Body weight (BW) was affected by Run; the interaction between OC and Run was significant. Running groups had higher BW than sedentary group. OC-Sed mice had lower BW than Veh-Run and Veh-Sed. OC-Run mice had higher BW than Veh-Run. Food intake decreased temporarily after pump implantation but was not affected by OC or Run. Organ and muscle weights were unaffected by either factor. Discussion: Voluntary physical activity improved GS in aged mice. This improvement was independent on unOC, which did not influence voluntary activity or muscle strength. Changes in BW were not associated with muscle mass and did not translate into function benefits. These findings suggest that unOC does not relevantly influence muscle function, whereas mechanical loading has a positive effect in aged mice. Further analyses of muscle structure and metabolism are underway to validate these findings.