Projects - J (Jingyi) Song MSc

Skeletal muscle mass and function decline with age. The cause for this is poorly understood. Neuromuscular junctions (NMJs) may play a role in this. NMJs are essential for muscle contraction and show age-associated degeneration in structure and function. To fulfill their function NMJs are densely packed with mitochondria for their energy supply. Aging is associated with reduced muscle oxygen availability (hypoxia) leading to a decreased mitochondrial function and increased production of reactive oxygen species (ROS). We hypothesize that this disrupts redox homeostasis leading to the observed deterioration of NMJs and consequently to loss of muscle function with age. ROS have a role in signaling, but also can cause damage. Healthy cells maintain redox homeostasis by actively balancing ROS production and ROS detoxification, using NADPH dependent antioxidant defense systems. Nicotinamide nucleotide transhydrogenase (NNT) is a major mitochondrial source of NADPH and plays important role in regulating mitochondrial redox homeostasis and aging. To investigate the role of redox homeostasis in NMJ function in aging, we will make use of a unique mouse model with Nnt+/+ (wild type) and Nnt-/- (knockout) in an identical genetic background and our ability to expose mice to mild environmental hypoxia, mimicking limited oxygen availability in aging. NMJs of mice of both genotypes and sexes will be examined with time (day 25, months 3 and 18) with and without a hypoxia challenge. In addition, ex vivo studies will be performed with skeletal muscles from different ages to mechanistically investigate the role of redox homeostasis in NMJ morphology and function.