Abstract
The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2-q21.3. Here we report that the trisomy and the monosomy of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy number variation in the Hspa13-App region has a peripheral impact on locomotor activity by altering muscle function.
Highlights
Down syndrome (DS) and M21 are complex genetic conditions that arise from an altered dosage of genes on human chromosome 21 (Hsa21)
We observe the opposite changes in locomotion, muscle strength, and energetic balance in new mouse models of DS and M21 for the Hspa13-App proximal region of human chromosome 21
The differential expression analysis revealed downregulation of skeletal muscle genes controlling energetic metabolism, mitochondrial activity, and biogenesis in Ts3Yah, while upregulation of similar set of genes was found in Ms3Yah mice
Summary
DS and M21 are complex genetic conditions that arise from an altered dosage of genes on human chromosome 21 (Hsa). The phenotypes of M21 are variable among individuals and depend on the specific deleted region of Hsa. DS, with an incidence of one in 700 live births [13], is still the most common viable cause of chromosomal aneuploidy in humans and the most frequent genetic cause of intellectual disability. Motor impairments are prominent throughout life and may contribute to the delay in cognitive skills [15, 16]. Poor locomotor skills have been attributed to impaired coordinated input due to cerebellar dysfunction [17, 18] but might have a more complex origin combining deficit in balance and postural control, stiffness, reduced muscular strength, and hypotonia
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