Hypermetabolism in mice carrying a near-complete human chromosome 21

• Published in: eLife Vol. 12
• Main Authors: Sarver, Dylan C, Xu, Cheng, Rodriguez, Susana, Aja, Susan, Jaffe, Andrew E, Gao, Feng J, Delannoy, Michael, Periasamy, Muthu, Kazuki, Yasuhiro, Oshimura, Mitsuo, Reeves, Roger H, Wong, G William
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 30-05-2023; eLife Sciences Publications, Ltd
• Subjects: Aneuploidy; Animal models; Animals; Artificial chromosomes; Body composition; Body fat; Body temperature; Ca2+-transporting ATPase; Calcium - metabolism; Calories; Cell culture; Chromosome 21; Chromosomes and Gene Expression; Chromosomes, Human - metabolism; Cytoplasm - metabolism; Down syndrome; Electron transport; Energy expenditure; Energy Metabolism - physiology; futile cycle; Gene expression; Genetic engineering; Humans; Hyperactivity; hypermetabolism; Liver; Metabolism; Mice; Mitochondria; Muscle, Skeletal - metabolism; Musculoskeletal system; Physiology; Proteins; Proteolipids - metabolism; Sarcolipin; SERCA pump; Skeletal muscle; Thermogenesis; Thermogenesis - genetics; trisomy; sarcolipin; mouse; futile cycle; chromosomes; aneuploidy; trisomy; SERCA pump; gene expression; hypermetabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.86023

The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca
ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.