The experiments proposed are driven by the working hypothesis that the major decrements in the structural and functional properties of skeletal muscles that occur between maturity and old age, and particularly between old age and extreme old age, are a function of denervation of muscle fibers. Specific hypotheses have been formulated to probe the cellular and molecular biology of surgically- induced denervation in young rats and of age-induced denervation in extremely-old 34 month rats. Project #2 will contribute to the Overall Goals through the development of protocols for electrical stimuation of denervated muscles with implantable microstimulators; and the measurement of mechanical properties of single fibers, motor units and whole muscles, muscle grafts, and both nonstimulated and stimulated denervated muscles. Following denervation, specific time periods are critical for cellular and molecular events underlying structural and functional recovery: within 10 days, the signaling cascades change the levels of expression of EF1alpha, S1, nAChR isoforms, and MRFs; and within 1 month, 70% of the muscle mass and 90% of the force are lost. Compared with immediately reinnervated muscles, reinnervation following 2 months of denervation results in 100% recovery, but recovery falls to 40% after 4 months and 20% after 7 months. Electrical stimulation of denervated muscles maintains muscle mass at 70% and force at 50% of control value. Based on these observations, both nonstimulated and stimulated-denervated muscles will be studied after periods of 10 days, 1, 2, 4 and 7 months. Project #2 will collaborate in the correlation of morphological cellular and molecular events with deficits and recovery in force and power of nonstimulated-denervated and stimulated-denervated muscles. The hypothesis to be tested is that selective denervation of fast fibers in muscles of extremely-old compared wit old rats will cause dramatic motor unit loss and remodeling. Severe motor unit loss is also expected following the grafting of EDL muscles from extremely old compared with old donor rats into young hosts. The interactions of fast and slow fiber types, fast and slow motor nerves, and the age of the rats on the success of reinnervation and regeneration will be investigated through self-innervation and cross-innervation of autografts of plantaris and soleus muscles. The combination of cellular and molecular probes and signaling processes with single fiber, motor unit and whole muscle structure-function relationships provides an hierarchical approach which promises significant new insights into age- induced denervation atrophy of skeletal muscle.
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