Target-Derived Trophic Effect on Skeletal Muscle Innervation in Senescent Mice

In the present work, we tested the hypothesis that target-derived insulin-like growth factor-1 (IGF-1) prevents alterations in neuromuscular innervation in aging mammals. To explore this hypothesis, we studied senescent wild-type mice as a model of deficient IGF-1 secretion and signaling and S1S2 transgenic mice as a tool to investigate the role of sustained overexpression of IGF-1 in striated muscle in neuromuscular innervation. The analysis of the nerve terminal in extensor digitorum longus muscles from senescent mice showed that the decrease in the percentage of cholinesterase-stained zones (CSZ) exhibiting nerve terminal branching, number of nerve branches at the CSZ, and nerve branch points was partially or completely reversed by sustained overexpression of IGF-1 in skeletal muscle. Target-derived IGF-1 also prevented age-related decreases in the postterminal alpha-bungarotoxin immunostained area, as well as the reduction in the number and length of postsynaptic folds, and area and density of postsynaptic folds studied with electron microscopy. Overexpression of IGF-1 in skeletal muscle may account for the lack of age-dependent switch in muscle fiber type composition recorded in senescent mice. In summary, the use of the S1S2 IGF-1 transgenic mouse model allowed us to provide morphological evidence for the role of target-derived IGF-1 in spinal cord motor neurons in senescent mice.