Glycosaminoglycans treatment increases IGF-I muscle levels and counteracts motor neuron death: A novel nonanticoagulant action.
The present study shows that sciatic nerve crush in 2-day-old rats causes extensor digitorum longus (EDL) muscle atrophy and motor neuron loss and that treatment with glycosaminoglycans (GAGs) promotes muscle reinnervation, motor neuron survival, and markedly increases insulin-like growth factor-I (IGF-I) content in the denervated muscles. EDL muscle denervation-induced atrophy in saline-treated rats is progressive and reaches the greatest extent at 42 days after birth, which correlates with reduced EDL weight growth. There is also a partial reinnervation as shown by the number of reinnervated EDL muscle fibers (65.4% of control) and by the poor restoration of the indirect isometric twitch tension (62% of control) that is further reduced under tetanic stimulation (34% of control). The number of surviving motor neurons that innervate EDL muscle drops from 55 +/- 3 to 29 +/- 8. In GAGs-treated 42-day-old rats, the effects of neonatal nerve lesioning on EDL muscle atrophy and denervation are successfully reversed, and the isometric twitch tension and the capacity to hold tetanic stimulation are restored to almost control levels. The number of surviving EDL motor neurons is also increased to 43 +/- 4. Treatment with GAGs selectively affects IGF-I content in denervated hindlimb muscles, which is augmented from 7.02 +/- 0.71 ng/mg tissue to 25.72 +/- 0.7 in the EDL and from 3.2 +/- 0.18 to a robust 211 +/- 9.6 in the soleus.
Losa
M
M
Laboratory for Research on Pharmacology of Neurodegenerative Disorders, Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy.
Vergani
L
L
Lesma
E
E
Rossoni
G
G
Di Giulio
A M
AM
Vercelli
A
A
Torsello
A
A
Muller
E E
EE
Gorio
A
A
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006614:Hindlimb; D007334:Insulin-Like Growth Factor I / Q000187:drug effects* / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000473:pathology / Q000517:prevention & control; D009409:Nerve Crush; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D006025:Glycosaminoglycans; D007334:Insulin-Like Growth Factor I