Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model.
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.
Dobrowolny
Gabriella
G
Department of Histology and Medical Embryology, CE-BEMM and Interuniversity Institute of Myology, University of Rome "La Sapienza", 14 00161 Rome, Italy.
Giacinti
Cristina
C
Pelosi
Laura
L
Nicoletti
Carmine
C
Winn
Nadine
N
Barberi
Laura
L
Molinaro
Mario
M
Rosenthal
Nadia
N
Musarò
Antonio
A
D018171:Agrin / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002490:Central Nervous System / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism; D051763:PAX7 Transcription Factor; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000737:chemistry / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016138:Walking
D018171:Agrin; D003893:Desmin; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D020033:Protein Isoforms; D011950:Receptors, Cholinergic; C000606290:SOD1 protein, human; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019703:Calcineurin; D018995:Myosin Heavy Chains