No abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.

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.

No abstract

We hypothesized that a 10-s rest interval (at zero load) inserted between each load cycle would increase the osteogenic effects of mechanical loading near previously identified thresholds for strain magnitude and cycle numbers. We tested our hypothesis by subjecting the right tibiae of female C57BL/6J mice (16 wk, n = 70) to exogenous mechanical loading within a peri-threshold physiological range of strain magnitudes and load cycle numbers using a noninvasive murine tibia loading device. Bone responses to mechanical loading were determined via dynamic histomorphometry. More specifically, we contrasted bone formation induced by cyclic vs. rest-inserted loading (10-s rest at zero load inserted between each load cycle) by first varying peak strains (1,000, 1,250, or 1,600 micro epsilon) at fixed cycle numbers (50 cycles/day, 3 days/wk for 3 wk) and then varying cycle numbers (10, 50, or 250 cycles/day) at a fixed strain magnitude (1,250 micro epsilon). Within the range of strain magnitudes tested, the slope of periosteal bone formation rate (p.BFR/BS) with increasing strain magnitudes was significantly increased by rest-inserted compared with cyclical loading. Within the range of load cycles tested, the slope of p.BFR/BS with increasing load cycles of rest-inserted loading was also significantly increased by rest-inserted compared with cyclical loading. In sum, the data of this study indicate that inserting a 10-s rest interval between each load cycle amplifies bone's response to mechanical loading, even within a peri-threshold range of strain magnitudes and cycle numbers.