Affiliation:
1. Centre for Cancer Research Hudson Institute of Medical Research Clayton VIC Australia
2. Institute for Nutrition Research, School of Health and Medical Sciences Edith Cowan University Perth WA Australia
3. Institute for Health and Sport (IHES) Victoria University Melbourne VIC Australia
4. Australian Institute for Musculoskeletal Science (AIMSS) The University of Melbourne, Victoria University and Western Health Melbourne VIC Australia
5. Department of Physiology University of Sydney Sydney NSW Australia
6. Dr Joseph Kaufmann Chair in Geriatric Medicine, Department of Medicine McGill University Montreal QC Canada
7. Research Institute of the McGill University Health Centre Montreal QC Canada
Abstract
AbstractImmobilization leads to muscle wasting and insulin resistance, particularly during ageing. It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti‐osteoporosis treatment, might protect muscle wasting independent of ucOC. We hypothesize that the combination of ucOC and ibandronate (IBN) treatments has superior protective effects against immobilization‐induced muscle wasting and insulin resistance than either treatment alone. C57BL/6J mice were hindlimb‐immobilized for two weeks, with injections of vehicle, ucOC (90 ng/g daily) and/or IBN (2 μg/g weekly). Insulin/oral glucose tolerance tests (ITT/OGTT) were performed. Immediately after immobilization, muscles (extensor digitorum longus (EDL), soleus, tibialis anterior, gastrocnemius and quadriceps) were isolated and measured for muscle mass. Insulin‐stimulated glucose uptake (EDL and soleus) was examined. Phosphorylation/expression of proteins in anabolic/catabolic pathways were examined in quadriceps. Primary human myotubes derived from older adult muscle biopsies were treated with ucOC and/or IBN, then signalling proteins were analysed. Combined treatment, but not individual treatments, significantly increased the muscle weight/body weight ratio in immobilized soleus (31.7%; P = 0.013) and quadriceps (20.0%; P = 0.0008) muscles, concomitant with elevated p‐Akt (S473)/Akt ratio (P = 0.0047). Combined treatment also enhanced whole‐body glucose tolerance (16.6%; P = 0.0011). In human myotubes, combined treatment stimulated greater activation of ERK1/2 (P = 0.0067 and 0.0072) and mTOR (P = 0.036), and led to a lesser expression of Fbx32 (P = 0.049) and MuRF1 (P = 0.048) than individual treatments. These findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing.
imageKey points
It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism.
Bisphosphonates, an anti‐osteoporosis treatment, might protect against muscle wasting independent of ucOC.
The combination treatment of ucOC and ibandronate was shown to exert a greater therapeutic effect against immobilization‐induced muscle wasting, and led to greater activation of anabolic pathway and less expression of catabolic signalling proteins in myotubes derived from older adults, compared with individual treatments.
The combination treatment was found to improve whole‐body glucose tolerance.
Our findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing.