Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease 
characterized by a selective degeneration of motor neurons, atrophy, and 
paralysis of skeletal muscle. Although a significant proportion of familial ALS 
results from a toxic gain of function associated with dominant SOD1 mutations, 
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 
integrity and enhanced satellite cell activity in SOD1(G93A) transgenic mice, 
inducing calcineurin-mediated regenerative 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 establish 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.