Reactive oxygen species and oxidative stress have been implicated in the etiology of age related loss of muscle mass and function. To investigate the role of chronic oxidative stress in vivo, we used a mouse model that lacks CuZnSOD (Sod1-/-), a major antioxidant enzyme. Sod1-/- mice are characterized by very high levels of oxidative stress and damage and show an acceleration of age-related loss of skeletal muscle mass. Mitochondrial isolated from skeletal muscle of Sod1-/- mice show reduced production of ATP, lower oxygen consumption, elevated levels of mitochondrial ROS and an increase in the mitochondrial apoptosis pathway. Despite alterations in mitochondrial function, skeletal muscle from Sod1-/- mice appear to have an increase in the number of mitochondria by electron microscopy and we measured an increase in mtDNA content. The mitochondrial permeability transition is induced more rapidly in muscle mitochondria from Sod1-/- mice with a greater release of the proapoptotic proteins, cytochrome c and AIF. Caspase-3 activity and the level of apoptotic nuclei measured using a cell free apoptosis system are also elevated in Sod1-/- mice. There is a loss of myonuclei and a reduction in fiber size that is associated with disruption of postsynaptic endplates in Sod1-/- mice. The synaptic cleft is altered and acetylcholine receptors (AChR) are significantly disorganized. The level of AChr protein is decreased while AChR mRNA levels are dramatically increased in conjunction with a significant increase in the percentage of denervated neuromuscular junctions reaching 80% at 20 months of age. Consistent with fragmentation of the AChR, the activity of calpain is increased and the level of rapsyn, a protein that functions to maintain AchR integrity, is significantly reduced in muscle from the Sod1-/- mice. The subsarcolemmal population of mitochondria, which function to support neuromuscular transmission, also exhibit a dramatic decline in ATP generation with concomitant increase in ROS generation. Overall, these data suggest that mitochondrial function and dyregulation of oxidative stress play an important role in age related skeletal muscle atrophy though disruption of the neuromuscular junction.