Background Immobilisation leads to muscle wasting, which may cause insulin resistance. Undercarboxylated osteocalcin (ucOC) is suggested to improve muscle mass and glucose metabolism. Bisphosphonates were recently reported to protect against muscle wasting, independent of ucOC. We tested the hypothesis that combination treatment with ucOC and bisphosphonates exerts a superior protective effect against immobilisation-induced muscle wasting than either treatment alone, while also improves glucose metabolism.
Methods 11-W-old C57BL/6 mice were subjected to hind-limb immobilisation for two weeks, during which ucOC (90ng/g; intraperitoneal) and/or ibandronate (2ug/g; subcutaneous) injections, Insulin tolerance test, and oral glucose tolerance test (OGTT) were performed. After immobilisation, muscles (extensor digitorum longus [EDL], soleus, tibialis anterior, gastrocnemius and quadriceps) were excised, and muscle weight was measured. Glucose uptake in EDL and soleus muscles was assessed. Proteins in anabolic/catabolic pathways were examined in the quadriceps muscle. In addition, older adults-originated primary myotubes treated with ucOC and/or IBN were analysed for the same signalling proteins.
Results Compared with vehicle, individual treatment with ucOC or ibandronate had minimal effect on hind immobilisation-induced muscle wasting (p>0.05), while combination treatment increased weight in immobilised soleus (31.7%; p<0.05) and quadriceps (20.0%; p<0.01) muscles, concomitant with elevated p-Akt (S473)/Akt ratio (p<0.05). Although combination treatment had limited effects on muscle glucose uptake in immobilised muscles (p>0.05), it enhanced whole-body glucose tolerance assessed via OGTT (16.6%; p<0.001). In human myotubes, combination treatment stimulated greater activation of ERK1/2 and mTOR, and led to a lesser expression of MuRF1, than individual treatments (all p<0.05).
Conclusions Combination treatment with ucOC and ibandronate exerts protective effects on immobilisation-induced muscle wasting in mice, and regulatory effects on anabolic/catabolic pathways in myotubes of older adults. Furthermore, combination treatment improves whole-body glucose tolerance. These findings suggest a therapeutic potential of combination treatment with ucOC and bisphosphonates for treating muscle wasting induced by immobilisation and ageing.