Recovery from disuse osteopenia coincident to restoration of muscle strength in mdx mice

Abstract

The objective of this study was to compare the tibial structure and the strength of the tibia during muscle weakness and after recovery in mdx mice (which demonstrate X-linked muscular dystrophy and subsequent muscle regeneration) and age-matched control mice. The extent of disuse atrophy produced by muscle weakness and recovery following restoration of normal muscle strength could then be determined. The tibiae adjacent to weakened tibialis anterior muscles of 4-week-old mdx mice had significantly reduced radiographic density ( p < 0.05) and cortical thickness ( p < 0.001), and increased porosity ( p < 0.001) compared to age-matched controls, suggesting development of disuse osteopenia. Significantly less force was required to break mdx tibiae than age-matched control tibiae ( p < 0.05). In addition, Sharpey's fiber density was reduced ( p < 0.001), suggesting a weakened attachment of the tibialis anterior muscle to bone. At 12 weeks, during the period of muscle regeneration, mdx tibial cortical thickness ( p < 0.001) and porosity ( p < 0.01) remained significantly lower, but percent calcium and Sharpey's fiber and radiographic densities were significantly greater ( p < 0.001) than in age-matched controls, suggesting that bone mineralization and muscle attachment strength had increased to above normal levels in parallel with recovery of strength by the attached muscle. By 18 weeks, mdx tibial cross-sectional area, cortical thickness, and porosity remained significantly less ( p < 0.001) than normal. Although Sharpey's fiber density was greater than in agematched controls ( p < 0.001) by 18 weeks, mdx tibial percent calcium ( p < 0.005) and Sharpey's fiber density ( p < 0.001) were significantly reduced from levels in 12-week-old mdx animals. There was significantly less deformation of the tibia prior to fracture in mdx than control tibiae at 18 weeks of age, suggesting tibial brittleness. Thus, at the site of attachment of mdx muscle to osteopenic bone, the remodelling which accompanies recovery of muscle strength is atypical, and produces an attachment of greater strength than function appears to require. These observations suggest that data are needed regarding bone mass and muscle—bone attachments in humans with disuse osteopenia, DMD, and other neuromuscular diseases.