? CORE B The Animal Resource Core (Core B) will provide the three Projects with unique mouse models to study potential mechanisms underlying muscle fiber loss that occurs during age-associated sarcopenia. These models will be based on the sarcopenia phenotype we discovered in the Cu/Zn-superoxide dismutase knockout mice (Sod1KO) and the unique, conditional knockout mouse that we have generated, which allows one to study the conditional expression of Sod1 on loss of muscle mass and function.
The specific aims of Core B are:
Specific Aim 1. Maintain aging colonies of male wildtype (WT) and Sod1KO mice for the Projects. The WT and Sod1KO mice generated by the Core will be maintained until they are 8, 15, and 29 months of age at which time they will be distributed to the three Projects for use in specific experiments.
Specific Aim 2. Generate and maintain colonies of male mice (8 and 15 months of age) in which Sod1 expression is conditionally expressed in neurons. (1) Mice lacking Sod1 in neurons will be generated by crossing Sod1flox/flox mice to transgenic mice that express the neuron-specific nestin-cre. (2) Mice lacking Sod1 in neurons and muscle will be generated by crossing transgenetic mice expressing the neuron-specific nestin- cre and the muscle specific acta-cre to Sod1flox/flox mice. (3) Mice that specifically express Sod1 only in neurons will be generated by crossing transgenic mice that express human SOD1 cDNA in neurons to Sod1KO mice.
Specific Aim 3. Generate and maintain colonies of male mice (8 and 15 months of age) in which antioxidant enzymes are conditionally expressed in skeletal muscle. (1) Mice lacking either Sod1 or Sod2 in muscle will be generated by crossing transgenetic mice expressing the muscle specific cre- recombinase, acta-cre to either Sod1flox/flox or Sod2flox/flox mice. (2) Transgenic mice expressing catalase only in muscle mitochondria will be obtained by crossing acta-cre transgenic mice to mice containing human catalase cDNA containing a mitochondria targeting signal and a floxed stop signal. (3) mMtCAT-Tg mice will be crossed to Sod1KO and acta-cre transgenic mice to produce Sod1KO mice expressing catalase in muscle mitochondria.
Specific Aim 4. Generate novel mouse models to explore novel mechanism that could play a role in the loss of muscle mass in Sod1KO mice. (1) Mice lacking Agrin in the motor neurons of mice will be generated to determine if a disruption of neuromuscular junctions will produce a sarcopenia phenotype. (2) NF- kB reporter mice will be used to measure NF-kB activation in the various animal models. (3) The p16-3MR mouse will be used to study the potential role of cell senescence in sarcopenia. (4) Mice overexpressing a mutated SOD1 transgene in neurons of Sod1KO mice will be generated to study the mechanism whereby Sod1 expression in neurons rescues the sarcopenia phenotype.
