Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upon touch, twitch once zebrafish respond with one or two swimming strokes instead of typical full-blown escapes. This use-dependent fatigue is shown to be a consequence of a mutation in the tetratricopeptide domain of muscle rapsyn, inhibiting formation of subsynaptic acetylcholine receptor clusters. Physiological analysis indicates that reduced synaptic strength, attributable to loss of receptors, is augmented by a potent postsynaptic depression not seen at normal neuromuscular junctions. The synergism between these two physiological processes is causal to the use-dependent muscle fatigue. These findings offer insights into the physiological basis of human myasthenic syndrome and reveal the first demonstration of a role for rapsyn in regulating synaptic function.
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PMID:The Zebrafish motility mutant twitch once reveals new roles for rapsyn in synaptic function. 1215 28

Rapsyn-deficient myasthenic syndrome is characterized by a weakness in voluntary muscle contraction, a direct consequence of greatly reduced synaptic responses that result from poorly clustered acetylcholine receptors. As with other myasthenic syndromes, the general muscle weakness is also accompanied by use-dependent fatigue. Here, we used paired motor neuron target muscle patch-clamp recordings from a rapsyn-deficient mutant line of zebrafish to explore for the first time the mechanisms causal to fatigue. We find that synaptic responses in mutant fish can follow faithfully low-frequency stimuli despite the reduced amplitude. This is in part helped by a compensatory increase in the number of presynaptic release sites in the mutant fish. In response to high-frequency stimulation, both wild-type and mutant neuromuscular junctions depress to steady-state response levels, but the latter shows exaggerated depression. Analysis of the steady-state transmission revealed that vesicle reloading and release at individual release sites is significantly slower in mutant fish during high-frequency activities. Therefore, reductions in postsynaptic receptor density and compromised presynaptic release collectively serve to reduce synaptic strength to levels that fall below the threshold for muscle action potential generation, thus accounting for use-dependent fatigue. Our findings raise the possibility that defects in motor neuron function may also be at play in other myasthenic syndromes that have been mapped to mutations in muscle-specific proteins.
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PMID:Fatigue in Rapsyn-Deficient Zebrafish Reflects Defective Transmitter Release. 2779 41