FAILURE OF ADAPTATIONS TO CONTRACTIONS IN MUSCLES OF CUZNSOD NULL MICE

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Loss of approximately 40% of skeletal muscle mass and a reduction in the ability of the remaining skeletal muscle to generate maximum force between the ages of 50 and 80 is a major factor contributing to frailty in the elderly. Despite the enormity of the problem, little progress has been made in understanding factors responsible for the physical aspects of frailty. This project has the long term goal of providing mechanistic information aimed at developing preventive and therapeutic interventions to improve strength, mobility, independence and quality of life for elderly people. Increased levels of markers of oxidative damage are associated with the age-related decline in skeletal muscle mass and strength but little direct evidence that an increase in oxidative reactions causes the decline in muscle function. Previous reports from the program project indicated that SooTA mice lacking Cu.Zn superoxide dismutase (CuZnSOD) had increased oxidative damage with advancing age that correlated with an accelerated loss of muscle mass, reduced number of fibers, defects in motor neurons and a decreased muscle force generation in comparison with wild type (WT) mice. Quiescent muscles of adult Soc/f/" mice also had increased DMA binding activity of the transcription factors, NFicB and AP-1 and increased expression of cytoprotective proteins such as MnSOD. Muscles of adult SodT'' mice also failed to fully activate adaptive responses to the increased reactive oxygen species (ROS) generated by isometric contractions. These changes are all characteristic of muscles of old WT mice. In Project 3 we will determine whether the accelerated muscle aging in Sod"/7" mice and normal aging in WT mice are associated with an increase in cytosolic superoxide in muscle fibers and whether this leads to a failure in the adaptive responses of the muscle to non-damaging contractile activity or overt damage. The working hypothesis for this study is that skeletal muscles of SodT'' mice are exposed to a chronic increased cytosolic superoxide throughout their lifetime and that this increased oxidative stress accelerates the normal age-related loss in the adaptive responses of the muscle to non-damaging isometric contractions or overt damage., The following specific aims will be addressed: 1) To determine the effect of age or lack of CuZnSOD on the cytosolic activities of superoxide and other ROS in skeletal muscle; 2) To determine the effect of replacing CuZnSOD in skeletal muscle or motor neurons on the activities of superoxide and other ROS in skeletal muscle fibers of SodT'~ mice; 3) To determine the effect of age'and lack of CuZnSOD on adaptive responses of skeletal muscle to nondamaging isometric contractions; 4) To determine whether, during regeneration from damage, skeletal muscles from old WT mice and those from mice lacking CuZnSOD show a failure of activation of NFxB and AP-1 and a lack of complete skeletal muscle regeneration compared with adult WT mice.