Abstract: Sarcopenia (Greek; sarcos: flesh, and penia: poverty) is the pronounced muscle loss that affects the aging population. Sareopenia of the leg muscles results in loss of independence and increased morbidity in the elderly. Emphasizing hind limb motor function, this thesis investigates different aspects of aging and sarcopenia in a rodent model. After characterizing sarcopenia in a rodent model, the long standing notion that sarcopenia results from reduced IGF-I signaling was addressed. Sarcopenia was not associated with lack of ICF-I signaling components; instead the data indicate a regenerative phenotype, which was most pronounced in the most sarcopenic cases. These cases not only expressed high levels of myogenic transcription factors related to the activation, proliferation and maturation of muscle stem cells (satellite cells), but also large numbers of fibers expressing embryonic myosin showing that the initial steps of a regenerative program are activated. To identify mechanisms underlying these changes, the proteomic and genomic profile of sarcopenia was studied. A multitude of adaptations occur in skeletal muscle with aging; these changes are consistent with a model of compensatory regenerative activity where oxidative stress, disturbed innervation and DNA damage are likely to contribute to the imbalance between buildup and breakdown of skeletal muscle. These results were extended by testing if a signaling pathway common to muscular atrophy induced by a variety of conditions such as denervation, disuse and disease, was activated in sarcopenia as well. This pathway regulates Atrogin-1 and MuRF1, which are ubiquitin ligases involved in ubiquitination steps necessary for proteasomal degradation of myofibrillar proteins during atrophy. Atrogin-1 and MuRF1 transcripts were reduced in sarcopenia and the changes could be explained by changes in the levels and activity of signaling components (P13K, AKT, FOXO) regulating their expression. This lead to the conclusion that sarcopenia is not to equate with muscle atrophy induced by denervation, disuse or disease. Furthermore, the data suggest that She may be involved in this signaling. She is strategically involved in several pathways of relevance for aging, including the signaling pathways of IGF-I, the nerve growth factor family of neurotrophins and the GDNF family. The ShcA p66 isoform, affords cells sensitivity to oxidative stress, and genetic removal of SchA p66 results in a prolonged lifespan. Increased levels of ShcA (all isoforms), suggest an amplified trophic and mitogenic signaling, which may reflect a response to oxidative stress as well as repair processes in sarcopenia. Pursuing the data indicating disturbed innervation, GDNF signaling components were studied in sarcopenia. Reflecting the interdependency of nerve and muscle, a number of signals are exchanged at the neuromuscular junction. GDNF provides trophic support to motoneurons and is active in the establishment and maturation of neuromuscular connections. The results suggest a compensatory increase in the muscle to nerve GDNF signaling during aging, which may help to explain why motor neurons are fairly well preserved in senescence despite the gradual loss of target muscle with advancing age. However, in contrast to young adult denervated skeletal muscle, aged skeletal muscle becomes depleted of GDNF protein in spite of the transcriptional upregulation. A key event in restoring function to regenerated muscle is reestablishment of innervation, which is necessary for the switch from embryonic to adult myosin isoforms. Thus, data previously interpreted as resulting solely from denervation, may also reflect the failing reinnervation of regenerated fibers.
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