Abstract
The development of spinal curvature deformities is a hallmark of muscular dystrophy. While glucocorticoid treatment has been shown to prolong muscle function in dystrophic mice, its effects on the development of dystrophinopathic spinal deformation are poorly understood. In this study, we test the effects of glucocorticoid treatment on the onset of thoracolumbar kyphosis in the dystrophin-deficient mdx mouse using voluntary running exercise to exacerbate muscle fibrosis. We measure the kyphotic index, erector spinae muscle fibrosis, and vertebral bone histomorphometry in 4-month-old mdx mice in four groups: sedentary control, exercise-treated (continuous voluntary access to an activity wheel), glucocorticoid-treated, and glucocorticoid + exercise-treated. Exercise treated mice were found to have significantly lower kyphotic index (i.e., greater kyphosis) and greater muscle fibrosis relative to controls (p < 0.05). However, the deleterious effect of exercise on KI and muscle fibrosis was prevented by glucocorticoid treatment. Some differences in bone histological parameters were observed between treatment groups, suggesting there is a complex relationship between dystrophic muscular changes and vertebral bone mass. Our findings indicate glucocorticoid treatment delays the onset of thoracodorsal spinal deformation in mdx mice.
Highlights
Mdx mice have a mutation in the gene that codes for dystrophin, an intracellular protein that anchors the actin cytoskeleton of striated muscle fibers to the extracellular matrix.[12]
One consequence of dystrophinopathic muscle degeneration in both mdx mice and humans is the development of spinal deformities. 56789 In the mdx mouse, spinal deformation generally appears in the form of pathological thoracolumbar kyphosis after 4 months of age, and becomes significantly pronounced relative to control mice by 9 months of age.[7]
Because functional decline of dystrophic striated muscle precedes muscle fibrosis in the mdx mouse,[29] we can infer that significant impairment of erector spinae muscle function occurred in the exercised mice in our study
Summary
Mdx mice have a mutation in the gene that codes for dystrophin, an intracellular protein that anchors the actin cytoskeleton of striated muscle fibers to the extracellular matrix.[12]. 56789 In the mdx mouse, spinal deformation generally appears in the form of pathological thoracolumbar kyphosis after 4 months of age, and becomes significantly pronounced relative to control mice by 9 months of age.[7] In humans, spinal deformities are a serious clinical concern because they contribute to respiratory dysfunction, the leading cause of death in Duchenne muscular dystrophy (DMD).1011. We test the effects of glucocorticoid treatment on the severity of thoracolumbar kyphosis in the mdx mouse. The use of voluntary exercise to exacerbate the symptoms of dystrophinopathy in the mdx mouse to more closely resemble DMD is common in studies of dystrophic pathophysiology and for pre-clinical testing of therapeutic interventions.171819. A treatment period of 4-weeks is used because long-term treatment with voluntary exercise (i.e., greater than 2 months) does not have the same deleterious effect in the mdx, and may even improve muscle function.212223 Voluntary wheel running was preferred over treadmill running because it is less invasive, more cost-effective and time-effective, and yet still provides the desired results
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