Related Experiment Videos
Plasminogen activators in the neuromuscular system of the wobbler mutant mouse
B Blondet1, G Barlovatz-Meimon, B W Festoff
1INSERM U. 153, CNRS URA 614, Paris, France.
Abstract:
Wobbler, the neurological mutant mouse, carries an autosomal recessive gene (wr) and has been characterized as a model of lower motoneuron disorders with associated muscle atrophy, denervation and reinnervation. During normal murine neuromuscular development a decrease in muscle plasminogen activator (PA) activity accompanies synapse maturation. In contrast, experimental denervation in adult mice leads to an increase in muscle PA activity. The purpose of the present study was to determine the possible involvement of PAs in the denervation/reinnervation phenomena and motoneuron degeneration that characterize the wobbler mutant mouse. We determined the degree of innervation and its characteristics in wobbler mice by measuring choline acetyltransferase (ChAT) activity. We measured ChAT in the spinal cord as well as in two different muscles known to be differentially affected, biceps brachii and gastrocnemius. We found a sharp decrease of ChAT activity in both muscles but not in spinal cord extracts. We estimated the extent of sprouting by the silver/cholinesterase stain. Motoneuron terminal sprouting, not detected in normal animals, was present in 40% of the neuromuscular junctions in wobbler mice. We estimated specific PA activities in biceps brachii and gastrocnemius muscle extracts, as well as spinal cord extracts, using both an amidolytic assay and fibrin zymography. Increased PA, predominantly urokinase-PA (uPA), was observed in wobbler mouse muscle. A greater uPA was detected in biceps brachii muscle than in gastrocnemius muscle, which is less impaired by the mutation. There was no change in spinal cord PA, although tissue type PA (tPA) is the predominant PA type there.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
In wobbler mice, a model for lower motoneuron disorders, increased muscle plasminogen activator (PA) activity, particularly urokinase-type PA (uPA), correlates with denervation and reinnervation. This contrasts with normal development and experimental denervation, highlighting uPA
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The wobbler mouse model exhibits lower motoneuron degeneration, muscle atrophy, denervation, and reinnervation.
- Plasminogen activator (PA) activity typically decreases during normal neuromuscular synapse maturation.
- Experimental denervation in adult mice increases muscle PA activity.
Purpose of the Study:
- To investigate the role of PAs in the denervation/reinnervation processes and motoneuron degeneration observed in wobbler mice.
- To assess PA involvement in the specific pathological changes characteristic of the wobbler mutation.
Main Methods:
- Choline acetyltransferase (ChAT) activity was measured in spinal cord and muscle (biceps brachii, gastrocnemius) to assess innervation.
- Motoneuron terminal sprouting was evaluated using silver/cholinesterase staining.
- Specific PA activities in muscle and spinal cord extracts were determined using amidolytic assays and fibrin zymography.
Main Results:
- Wobbler mice showed significantly decreased ChAT activity in biceps brachii and gastrocnemius muscles, but not in spinal cord.
- Motoneuron terminal sprouting was observed in 40% of neuromuscular junctions in wobbler mice.
- Increased PA activity, predominantly urokinase-type PA (uPA), was found in wobbler mouse muscles, with higher levels in the more affected biceps brachii.
Conclusions:
- Plasminogen activators, especially uPA, are implicated in the denervation and reinnervation phenomena of the wobbler mouse model.
- The differential increase in uPA activity between muscles correlates with the varying severity of impairment caused by the wobbler mutation.
- These findings suggest a specific role for muscle-derived uPA in the pathophysiology of this lower motoneuron disorder.