Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model.
In the slow-channel syndrome (SCS) mutant acetylcholine receptors elicit calcium overload and myonuclear degeneration at the neuromuscular junction (NMJ), without muscle fiber death. Activated caspases are present at SCS motor endplates. We hypothesized that SCS represents a limited form of apoptosis. We found condensed chromatin and occasional single-strand DNA nicks in degenerating synaptic nuclei. Cleaved forms of caspases-3 and -9 were present in mouse SCS muscle homogenates and were specifically localized to NMJs. Finally, interruption of cholinergic activity by axotomy markedly reduced NMJ caspase activity and improved the morphological features of apoptosis at NMJs. These results demonstrate that in SCS processes leading to apoptosis may remain compartmentalized and reversible. Use of cysteine protease inhibitors may aid in treatment of this and other dystrophic muscle and excitotoxic disorders. Identification of extrasynaptic factors that prevent the spread of apoptosis in SCS muscle fibers may aid in developing treatments for neurological disorders characterized by excitotoxicity or apoptosis.
Vohra
Bhupinder P S
BP
Washington University School of Medicine, Department of Pediatrics, St. Louis, MO 63110, USA.
Groshong
Jason S
JS
Zayas
Roberto
R
Wollmann
Robert L
RL
Gomez
Christopher M
CM
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018482:Muscle, Skeletal / Q000294:innervation* / Q000473:pathology; D020294:Myasthenic Syndromes, Congenital / Q000473:pathology*; D011950:Receptors, Cholinergic / Q000235:genetics*
D011950:Receptors, Cholinergic; D002118:Calcium