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Published 18 January 2005. doi:10.1083/jcb.200407021
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 2, 193-199
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Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model



Gabriella Dobrowolny1, Cristina Giacinti1, Laura Pelosi1, Carmine Nicoletti1, Nadine Winn2, Laura Barberi1, Mario Molinaro1, Nadia Rosenthal2, and Antonio Musarò1,3

1 Department of Histology and Medical Embryology, CE-BEMM and Interuniversity Institute of Myology, University of Rome "La Sapienza", 14 00161 Rome, Italy
2 EMBL Mouse Biology Program, 00016 Monterotondo, Italy
3 Edith Cowan University, 6027 Western Australia

Correspondence to Antonio Musarò: antonio.musaro{at}uniroma1.it; or Nadia Rosenthal: rosenthal{at}embl-monterotondo.it


Abstract

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 SOD1G93A 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 SOD1G93A 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.

Abbreviations used in this paper: AChR, acetylcholine receptor; ALS, amyotrophic lateral sclerosis; CnA, calcineurin; GFAP, glial fibrillary acidic protein; Igf, insulin-like growth factor; mIgf-1, local isoform of Igf-1; MyHC, myosin heavy chain; SOD1, superoxide dismutase1; wt, wild-type.


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