GDNF expression is increased in denervated human skeletal muscle.

Glial cell line derived neurotrophic factor (GDNF) is a potent trophic factor for several subpopulations of neurons including motor neurons. Two different transcripts of the GDNF gene (GDNF633 and GDNF555) have been detected in various tissues, including skeletal muscle. Denervation leads to an upregulation of GDNF633 in rat skeletal muscle, indicating that GDNF is involved in the response of skeletal muscle to denervation and possibly in reinnervation. To determine the role of GDNF in human neuromuscular disease, we investigated the expression of both transcripts in normal and denervated muscle and in muscle biopsies from Duchenne muscular dystrophy patients. GDNF expression levels were analyzed by competitive RT-PCR in 38 muscle specimens. Levels of both transcripts were significantly elevated in denervated muscle compared to normal and dystrophic muscle. Morphometric analysis of muscle-fiber calibers and its correlation to GDNF expression revealed that higher levels of GDNF were expressed in rapidly-progressive neurogenic atrophy, including four amyotrophic lateral sclerosis (ALS) cases, compared to cases of chronic atrophy. In dystrophic muscle, transcript levels were not significantly altered compared to normal controls. These data indicate that denervation, but not dystrophy, enhances GDNF expression in human skeletal muscle. Thus, the increase of GDNF expression is part of the reaction of human skeletal muscle to denervation caused by motor nerve lesion. GDNF might act on regenerating nerve fibers during muscle fiber reinnervation.