Mammalian Lifespan Control: Phenotypes of Cisd2 Overexpression and Muscle-specific Knockout in Mice

• Main Authors: Chia-Yu Wu, 吳家瑜
• Other Authors: Ting-Fen Tsai
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/58079062660079819886

博士 === 國立陽明大學 === 生命科學系暨基因體科學研究所 === 100 === CISD2 gene, which is an evolutionarily conserved gene, encodes a transmembrane protein primarily associated with the mitochondrial outer membrane. Significantly, the CISD2 gene is located within the candidate region on chromosome 4q where a genetic component for human longevity has been mapped. Additionally, an age-dependent decrease in Cisd2 expression has been detected during normal aging. In order to investigate the role of Cisd2 in longevity, we generate Cisd2 transgenic mice carrying Cisd2 coding region controlled by RNA polymerase II large subunit (Pol II) promoter. A persistent Cisd2 expression can prolong lifespan without deleterious side effects and ameliorates age-related phenotypes in skin, muscle and neurons of the Cisd2 transgenic mice. We also detect mitochondrial DNA integrity, functions and different complexes activity and find that mitochondrial DNA deletion, oxygen consumption and complex I activity are rescued in 24-month old transgenic mice as compared with wild-type mice. Age-related decline of whole-body energy metabolism and locomotion activity are also rescued in transgenic mice indicating that persistent expression of Cisd2 can prolong lifespan and maintain healthy condition in old mice. Previously we have shown that Cisd2 deficiency shortens lifespan resulting in premature aging in mice. Most importantly, muscle and neuron degeneration are the earliest phenotypes in Cisd2 conventional knockout mice. To analyze whether muscle is the first aging tissue and drives systematic aging, we generate muscle specific Cisd2 knockout mice. Phenotypes analysis of this mouse, muscle and neuron degeneration are detected in 2-week old and decreases of body fat and bone mineral density are detected in 3-month old. I further investigated if there is a signal that is secreted by degenerating muscle and coordinates systematic defects of other non-muscle tissues. We find a hormone-like protein, fibroblast growth factor 21 (Fgf21), which is abnormally up-regulated in degenerating skeletal muscle and secreted to circulation. Fgf21 may be the key factor produced by damaging muscle that leads to systematic metabolic defects while the molecular mechanism is still under investigated.