Acetylcholine receptor epsilon-subunit deletion causes muscle weakness and atrophy in juvenile and adult mice.
In mammalian muscle a postnatal switch in functional properties of neuromuscular transmission occurs when miniature end plate currents become shorter and the conductance and Ca2+ permeability of end plate channels increases. These changes are due to replacement during early neonatal development of the gamma-subunit of the fetal acetylcholine receptor (AChR) by the epsilon-subunit. The long-term functional consequences of this switch for neuromuscular transmission and motor behavior of the animal remained elusive. We report that deletion of the epsilon-subunit gene caused in homozygous mutant mice the persistence of gamma-subunit gene expression in juvenile and adult animals. Neuromuscular transmission in these animals is based on fetal type AChRs present in the end plate at reduced density. Impaired neuromuscular transmission, progressive muscle weakness, and atrophy caused premature death 2 to 3 months after birth. The results demonstrate that postnatal incorporation into the end plate of epsilon-subunit containing AChRs is essential for normal development of skeletal muscle.
Witzemann
V
V
Abteilung Zellphysiologie, Max-Planck-Institut für medizinische Forschung, Heidelberg, Germany.
Schwarz
H
H
Koenen
M
M
Berberich
C
C
Villarroel
A
A
Wernig
A
A
Brenner
H R
HR
Sakmann
B
B
D000818:Animals; D000831:Animals, Newborn; D002678:Chimera; D003433:Crosses, Genetic; D004553:Electric Conductivity; D005260:Female; D005333:Fetus; D017353:Gene Deletion; D015698:Genomic Library; D006579:Heterozygote; D006720:Homozygote; D007537:Isometric Contraction; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008818:Mice, Neurologic Mutants; D009043:Motor Activity; D009045:Motor Endplate / Q000473:pathology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009468:Neuromuscular Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D011950:Receptors, Cholinergic / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D015183:Restriction Mapping; D013569:Synapses / Q000473:pathology / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics*; D014158:Transcription, Genetic
D011950:Receptors, Cholinergic