Progression of kyphosis in mdx mice

Abstract

Spinal deformity in the form of kyphosis or kyphoscoliosis occurs in most patients with Duchenne muscular dystrophy (DMD), a fatal X-linked disorder caused by an absence of the subsarcolemmal protein dystrophin. Mdx mice, which also lack dystrophin, show thoracolumbar kyphosis that progresses with age. We hypothesize that paraspinal and respiratory muscle weakness and fibrosis are associated with the progression of spinal deformity in this mouse model, and similar to DMD patients there is evidence of altered thoracic conformation and area. We measured kyphosis in mdx and age-matched control mice by monthly radiographs and the application of a novel radiographic index, the kyphotic index, similar to that used in boys with DMD. Kyphotic index became significantly less in mdx at 9 mo of age (3.58 +/- 0.12 compared with 4.27 +/- 0.04 in the control strain; P < or = 0.01), indicating more severe kyphosis, and remained less from 10 to 17 mo of age. Thoracic area in 17-mo-old mdx was reduced by 14% compared with control mice (P < or = 0.05). Peak tetanic tension was significantly lower in mdx and fell 47% in old mdx latissimus dorsi muscles, 44% in intercostal strips, and 73% in diaphragm strips (P < or = 0.05). Fibrosis of these muscles and the longissimus dorsi, measured by hydroxyproline analysis and histological grading of picrosirius red-stained sections, was greater in mdx (P < 0.05). We conclude that kyphotic index is a useful measure in mdx and other kyphotic mouse strains, and assessment of paralumbar and accessory respiratory muscles enhance understanding of spinal deformity in muscular dystrophy.

A cytoskeletal tropomyosin can compromise the structural integrity of skeletal muscle

“…Necrosis and fibrosis of the dorsal paraspinal and postural muscles (latissimus dorsi, intercostal and diaphragm muscles) has been reported for the dystrophic mdx (dystrophin null) and mdx/utrophin double KO mice [Lefaucheur et al, 1995;Deconinck et al, 1997;Grady et al, 1997]. Weakness in these muscles is thought to be a major contributor to the kyphosis that is seen in these mouse models [Deconinck et al, 1997;Grady et al, 1997;Laws and Hoey, 2004]. Kyphosis and other skeletal abnormalities were not observed in the Tm3 mice (data not shown).…”

Severe Extracellular Matrix Abnormalities and Chondrodysplasia in Mice Lacking Collagen Prolyl 4-Hydroxylase Isoenzyme II in Combination with a Reduced Amount of Isoenzyme I

“…To assess the degree of kyphosis, full body scans were performed using 35-m isotropic voxel size. The kyphotic index, a measure of spine deformity, was calculated as described previously (18). Briefly, kyphotic index ϭ AB/CD, where AB is the distance between the bodies of the first sacral and first thoracic vertebrae, and CD is the greatest distance from the line AB to the vertebral body.…”

Muscle stem cells in development, regeneration, and disease

“…The phenotypic changes in the mdx mouse model are less pronounced compared with the DMD patients, but the mutant mouse has ongoing cycles of degeneration and regeneration of skeletal muscle (peaking at 3-10 wk of age) and an increase in fat and fibrosis of the skeletal muscle (Bell and Conen 1968;DiMario et al 1991;Matsuda et al 1995;Straub et al 1997;Briguet et al 2004). The mdx mice also have spinal abnormalities (i.e., kyphosis) and a dilated cardiomyopathy (Briguet et al 2004;Laws and Hoey 2004;Quinlan et al 2004). A genetic mouse model that may have a more severe myopathy and limited survival is the utrophindystrophin double-mutant mice (Deconinck et al 1997).…”