Interdependence of Muscle Atrophy and Bone Loss Induced by Mechanical Unloading

Abstract

Mechanical unloading induces muscle atrophy and bone loss; however, the time course and interdependence of these effects is not well defined. We subjected 4-month-old C57BL/6J mice to hindlimb suspension (HLS) for three weeks, sacrificing 12-16 mice on day (D) 0, 7, 14, and 21. Lean mass was 7-9% lower for HLS vs. control from D7-21. Absolute mass of the gastrocnemius (gastroc) decreased 8% by D7, and was maximally decreased 16% by D14 of HLS. mRNA levels of Atrogin-1 in the gastroc and quad were increased 99% and 122%, respectively, at D7 of HLS. Similar increases in MuRF1 mRNA levels occurred at D7. Both atrogenes returned to baseline by D14. Protein synthesis in gastroc and quad was reduced 30% from D7-14 of HLS, returning to baseline by D21. HLS decreased phosphorylation of SK61, a substrate of mammalian target of rapamycin (mTOR), on D7-21, while 4E-BP1 was not lower until D21. Cortical thickness of the femur and tibia did not decrease until D14 of HLS. Cortical bone of controls did not change over time. HLS mice had lower distal femur bone volume fraction (−22%) by D14; however, the effects of HLS were eliminated by D21 due to the decline of trabecular bone mass of controls. Femur strength was decreased approximately 13% by D14 of HLS, with no change in tibia mechanical properties at any time point. This investigation reveals that muscle atrophy precedes bone loss during unloading and may contribute to subsequent skeletal deficits. Countermeasures that preserve muscle may reduce bone loss induced by mechanical unloading or prolonged disuse. Trabecular bone loss with age, similar to that which occurs in mature astronauts, is superimposed on unloading. Preservation of muscle mass, cortical structure, and bone strength during the experiment suggests muscle may have a greater effect on cortical than trabecular bone.

Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

“…As in our previous study conducted on a smaller series, 13 we detected myogenic changes in addition to neurogenic atrophy in the majority of biopsies. We did not confirm any relationship of motor disability with the amount of myogenic pathology, even if, interestingly, the highest CAG repeat number (50) was measured in two mildly symptomatic patients with type III muscle pathology.…”

“…We were surprised by the relatively well-preserved spinal bone density compared with the increased frequency of low femoral BMD, this latter being even higher than in controls. A possible explanation might be that reduced mechanical load secondary to muscle weakness in the lower limbs—the most frequent site of disease onset—had led to femoral bone loss 50. However, the lack of correlation between DXA measures and functional scores argues against this hypothesis.…”

“…A possible explanation might be that reduced mechanical load secondary to muscle weakness in the lower limbs-the most frequent site of disease onset-had led to femoral bone loss. 50 However, the lack of correlation between DXA measures and functional scores argues against this hypothesis. Moreover, it would remain unexplained why bone density is preserved at the lumbar level compared with age-matched male patients.…”

From mechanical stimulus to bone formation: A review

“…This behaviour may explain why astronauts lose bone mass in a microgravity environment, where the need to maintain posture is absent, despite rigorous exercise, or why 3 h/day of quiet standing has been shown to prevent bone loss in bed rest patients [90,112,113].…”

Protective Effects of Controlled Mechanical Loading of Bone in C57BL6/J Mice Subject to Disuse

“…These conditions can lead to decreased mobility, reduced daily activities, lower quality of life, and increased risk for falls and fractures. Similarly, spaceflight can induce negative effects on bone and muscle . One year after returning to Earth, the femoral BMD of astronauts who had spent 4 to 6 months on the International Space Station had only partially recovered …”