Background: Muscle disuse leads to muscle atrophy and insulin resistance. Recent reports suggest that a bone-produced hormone undercarboxylated osteocalcin (ucOC), and bisphosphonates - a commonly used drug for osteoporosis, may improve muscle mass and insulin sensitivity. We tested whether ucOC and/or bisphosphonate (ibandronate) treatments prevents muscle wasting and insulin resistance during disuse conditions in mice.
Methods: Male C57BL/6 mice were subjected to single-leg immobilisation, or provided with free movement, for 14 days. During the immobilisation, mice were injected with placebo, ucOC, ibandronate, or ucOC combined with ibandronate. Insulin tolerance tests and oral glucose tolerance tests were performed on Day 10 and 12, respectively. After euthanasia, extensor digitorum longus (EDL) and soleus muscles were isolated and weighed, then immediately used in glucose uptake analysis. Tibialis anterior (TA), gastrocnemius, and quadriceps muscles were also isolated and weighed, then snap frozen for further analyses including Western Blot.
Results: ucOC exerted an overall anti-atrophic effect only on immobilised quadriceps muscle (ANOVA p < 0.001). Ibandronate had overall anti-wasting effects specifically on soleus muscle (ANOVA p = 0.0062) and TA muscle (ANOVA p = 0.049). The administration of ucOC combined with ibandronate exhibited better therapeutic effect than single administrations, improving soleus and quadriceps muscle mass by 31.7% and 19.9%. Furthermore, only the combination administration enhanced Akt phosphorylation in quadriceps muscle.
Hindlimb immobilisation did not affect whole-body glucose tolerance or insulin sensitivity, albeit reducing insulin response in soleus muscle. UcOC, but not ibandronate, had overall improving effects on glucose tolerance (ANOVA p = 0.014) and insulin sensitivity in immobilised soleus muscle (ANOVA p = 0.020).
Conclusion: ucOC and ibandronate reduce hindlimb immobilisation-induced muscle wasting and muscle insulin resistance in a muscle-specific manner, with combined administration demonstrating better therapeutic potential. Therefore, the effects of such administration on human muscle cells or tissue need to be further investigated.