Transient muscle paralysis disrupts bone homeostasis by rapid degradation of bone morphology

摘要

We have previously shown that transient paralysis of murine hindlimb muscles causes profound degradation of both trabecular and cortical bone in the adjacent skeleton within 3 weeks. Morphologically, the acute loss of bone tissue appeared to arise primarily due to osteoclastic bone resorption. Given that the loss of muscle function in this model is transient, we speculated that the stimulus for osteoclastic activation would be rapid and morphologic evidence of bone resorption would appear before 21 d. We therefore utilized high-resolution in vivo serial micro-CT to assess longitudinal alterations in lower hindlimb muscle volume, proximal tibia trabecular and tibia middiaphysis cortical bone morphology in 16 wk old female C57 mice following transient calf paralysis from a single injection of botulinum toxin A (BtA; 2U/100g body weight). In an acute study, we evaluated muscle and bone alterations at d 0, 3, 5 and 12 following transient calf paralysis. In a chronic study, following d 0 imaging, we assessed the recovery of these tissues following the maximum observed trabecular degradation (d 12) through d 84 post-paralysis. The time course and degree of recovery of muscle, trabecular and cortical bone varied substantially. Significant atrophy of lower limb muscle was evident by d 5 of paralysis, maximal at d 28 (−34.1 ± 0.9%) and partially recovered by d 84. Trabecular degradation within the proximal tibia metaphysis occurred more rapidly, with significant reduction in BV/TV by d 3, maximal loss at d 12 (−76.8 ± 2.9%) with only limited recovery by d 84 (−51.7 ± 5.1% vs. d 0). Significant cortical bone volume degradation at the tibia mid-diaphysis was first identified at d 12, was maximal at d 28 (−9.6 ± 1.2%), but completely recovered by d 84. The timing, magnitude and morphology of the observed bone erosion induced by transient muscle paralysis was consistent with a rapid recruitment and prolific activation of osteoclastic resorption. In a broader context, understanding how brief paralysis of a single muscle group can precipitate such rapid and profound bone resorption in an adjacent bone is likely to provide new insight into how normal muscle function modulates bone homeostasis.