Amyotrophic lateral sclerosis (ALS) is a progres- sive neurodegenerative disease characterized by a selective degeneration of motor neurons, atrophy, and paralysis of skeletal muscle. Although a sig- nificant proportion of familial ALS results from a toxic gain of function associated with dominant SOD1 muta- tions, the etiology of the disease and its specific cellular origins have remained difficult to define. Here, we show that muscle-restricted expression of a localized insulin- like growth factor (Igf) -1 isoform maintained muscle in- tegrity and enhanced satellite cell activity in SOD1 G93A transgenic mice, inducing calcineurin-mediated regener- ative pathways. Muscle-specific expression of local Igf-1 (mIgf-1) isoform also stabilized neuromuscular junctions, reduced inflammation in the spinal cord, and enhanced motor neuronal survival in SOD1 G93A mice, delaying the onset and progression of the disease. These studies estab- lish skeletal muscle as a primary target for the dominant action of inherited SOD1 mutation and suggest that muscle fibers provide appropriate factors, such as mIgf-1, for neuron survival.
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