Atrophy and weakness cause countless injuries through falls and impair the quality of life, yet the cause of muscle atrophy and weakness is unknown. The purpose is to determine the effect of a aerobic contraction protocol on the generation of reactive oxygen (ROS), ROS-induced damage and the adaptations of heat shock proteins (HSPs) in skeletal muscles of 8-month old (young/adult) and 28-month-old (old) mice. Comparisons will be made among wild type (WT) mice and knockout and transgenic mice with deficient or enhanced mitochondrial and cytosolic antioxidant systems. In aerobic organisms, ROS are generated constantly with 85% generated in the mitochondria and the remainder from extra mitochondrial sources. The antioxidant systems are complex, diverse and adaptable in both the mitochondria and the cytosol. Consequently, particularly in young healthy animals with intact or enhanced antioxidant systems, even with the increased ROS generation of a demanding contraction protocol, the generation of superoxide anion produces an ROS stress, but no ROS damage. In contrast, old animals, or animals with impaired antioxidant systems, ROS stress has the potential to produce damage at rest or with contraction protocols. The working hypothesis is that age (young/adult or old), metabolic status (quiescent or contracting), and antioxidant status (intact, mitochondrial or cytosolic knock out, or enhanced through conditioning of genetic modification), will interact on the magnitude of the ROS stress and the severity and permanence of the ROS damage. To test the working hypothesis rigorously, skeletal muscles of young/adult and old mice with intact antioxidant systems, or with antioxidant systems enhanced or impaired in either the mitochondria (SodTg+/0, Sod2+/- and Sod2D3-/- mice) or cytosol (Sod1+/- and Sod1-/- mice) will be compared while quiescent or following a demanding protocol of aerobic contractions. Five specific hypotheses will be tested that will provide major new insights as to the conditions of ROS stress and antioxidant status that lead to severe and permanent damage to skeletal muscle fibers following a demanding aerobic contraction protocol. Of great importance is the hypothesis that only mice with intact antioxidant systems will condition.
|Effective start/end date||4/1/02 → 4/30/15|
- National Institutes of Health
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