Abstract
Down syndrome, caused by trisomy 21, is characterized by a variety of medical conditions including intellectual impairments, cardiovascular defects, blood cell disorders and pre-mature aging phenotypes. Several somatic stem cell populations are dysfunctional in Down syndrome and their deficiencies may contribute to multiple Down syndrome phenotypes. Down syndrome is associated with muscle weakness but skeletal muscle stem cells or satellite cells in Down syndrome have not been investigated. We find that a failure in satellite cell expansion impairs muscle regeneration in the Ts65Dn mouse model of Down syndrome. Ts65Dn satellite cells accumulate DNA damage and over express Usp16, a histone de-ubiquitinating enzyme that regulates the DNA damage response. Impairment of satellite cell function, which further declines as Ts65Dn mice age, underscores stem cell deficiencies as an important contributor to Down syndrome pathologies.
Highlights
Trisomy 21, responsible for Down syndrome, is the most common autosomal aneuploidy and the most frequent genetic cause of intellectual disability[1,2,3]
We report that reduced satellite cell expansion impairs skeletal muscle regeneration in Ts65Dn mice
Ts65Dn satellite cell dysfunction may contribute to multiple Down syndrome muscle phenotypes providing additional evidence that somatic stem cell deficiencies contribute to Down syndrome phenotypes
Summary
Trisomy 21, responsible for Down syndrome, is the most common autosomal aneuploidy and the most frequent genetic cause of intellectual disability[1,2,3]. Stem cell defects in Down syndrome likely contribute to cognitive impairments, blood cell disorders, and pre-mature aging phenotypes in Down syndrome[10,11,12,13]. While satellite cell dysfunction contributes to a variety of diseases including muscular dystrophy, cancer cachexia and age-induced muscle wasting[20,21,22,23,24], whether Down syndrome trisomy affects satellite cells and contributes to Down syndrome muscle phenotypes is unknown. Since skeletal muscle dysfunction associated with Down syndrome includes muscle weakness, early onset age-induced atrophy and overall diminished mobility, Down syndrome trisomy may impact satellite cell function[25,26,27,28,29]. The impairment of satellite cell function in Ts65Dn mice provides further evidence that stem cell dysfunction is a common contributor to multiple Down syndrome phenotypes.
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