Abstract
Down syndrome (DS) is a genetically based disease caused by triplication of chromosome 21. DS is characterized by severe muscle weakness associated with motor deficits; however, understanding the DS-associated skeletal muscle condition is limited. In this study, we used a combined methodological approach involving light and electron microscopy, as well as nuclear magnetic resonance spectroscopy metabolomics, to investigate morphology and composition of the quadriceps muscles in the Ts65Dn mouse, a model of DS, to identify structural and/or functional trisomy-associated alterations. Morphometric analysis demonstrated a larger size of myofibers in trisomic versus euploid mice; however, myofibrils were thinner and contained higher amounts of mitochondria and lipid droplets. In trisomic mice, magnetic resonance spectroscopy showed a tendency to an overall increase in muscle metabolites involved in protein synthesis. These data strongly suggest that in DS, a sarcoplasmic hypertrophy associated with myofibril loss characterizes quadriceps myofibers. In addition, large-sized mitochondria suggestive of impaired fission/fusion events, as well as metabolites modifications suggestive of decreased mitochondrial function, were found in the trisomic muscle. Albeit preliminary, the results provided by this novel approach consistently indicate structural and compositional alterations of the DS skeletal muscle, which are typical of early aging.
Highlights
Down syndrome (DS) is a genetically based disease caused by triplication of chromosome 21 and affecting about 1 in 700 new borns (Parker et al, 2010)
The percentage of myofibers with central nuclei increased in the rectus femoris muscle of trisomic versus euploid mice at the limit of statistical significance
A similar proportion of fast and slow fibers was found in the muscle of euploid and trisomic Ts65Dn mice; instead, myofiber size was significantly greater in trisomic versus euploid mice
Summary
Down syndrome (DS) is a genetically based disease caused by triplication of chromosome 21 and affecting about 1 in 700 new borns (Parker et al, 2010). In addition to the numerous health conditions characterizing this syndrome, persons with DS exhibit severe muscle weakness associated with a deficit in motor coordination, balance, and postural control (Rigoldi et al, 2011; Malak et al, 2013). This significantly limits their daily life and functional work capacity (Carmeli et al, 2002a, 2002b; Cowley et al, 2010). A focus on animal models of DS that have translational relevance to humans would allow for studies of common and causal mechanisms involved in the muscular deficit of DS
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