Evidence of Mitochondrial Impairment in a Mouse Model of Down Syndrome

Cynthia Anyaoku, Lara R. DeRuisseau, Josef Brandauer

Research output: Contribution to journalArticlepeer-review

Abstract

INTRODUCTION: Down Syndrome (DS) is typically the result of triplication of the 21st chromosome. DS causes widespread developmental and physical changes to the body. One commonly observed physical change of DS is muscle weakness, which can contribute to difficulty in executing activities of daily living. Nicotinamide adenine dinucleotide (NAD) is an important determinant of skeletal muscle function and mitochondrial activity. Currently, it is unknown whether muscle weakness in those with DS is at least partially related to an imbalance of NAD or a lack of mitochondrial NAD usage. Nicotinamide phosphoribosyl transferase (Nampt) catalyzes the rate-limiting step in the mammalian NAD recycling pathway, while SIRT3 is an NAD-dependent protein deacetylase which regulates mitochondrial content and activity. We hypothesized the expression of these proteins would be decreased in Ts65Dn animals, an established mouse model of DS, relative to wild-type (WT) animals. METHODS: Diaphragm and left ventricle samples from 12- or 18-month-old male Ts65Dn mice and WT animals were pulverized and homogenized in ice-cold lysis buffer. Total lysate protein concentration was determined by Bradford assay. Samples were resolved in SDS gels, transferred to nitrocellulose membranes, and blotted for Nampt and SIRT3. Lysates were also separately analyzed for citrate synthase activity. RESULTS: Both Nampt (p = 0.02) and SIRT3 (p = 0.002) expression levels were significantly higher in WT than Ts65Dn ventricles at 12 months. In addition, SIRT3 levels were higher in diaphragm of 12-month-old WT animals (p = 0.02). Citrate synthase levels were similar in all tissues. CONCLUSION: Our findings of reduced Nampt protein suggest that reduced NAD recycling takes place in DS muscle tissue despite similar observed mitochondrial (citrate synthase) activity. These results suggest a role of diminished peripheral mitochondrial function and ATP synthesis in Down Syndrome muscle.

Original languageEnglish (US)
JournalFASEB Journal
Volume36
DOIs
StatePublished - May 1 2022

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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