Acetylcholine receptor ɛ-subunit deletion causes muscle weakness and atrophy in juvenile and adult mice

Acetylcholine receptor ɛ-subunit deletion causes muscle weakness and atrophy in juvenile and adult mice

^*Abteilung Zellphysiologie, Max-Planck-Institut für medizinische Forschung, 69120 Heidelberg, Germany; and ^§Physiologisches Institut, Universität Bonn, 53111 Bonn, Germany

Abstract

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 γ-subunit of the fetal acetylcholine receptor (AChR) by the ɛ-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 ɛ-subunit gene caused in homozygous mutant mice the persistence of γ-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 ɛ-subunit containing AChRs is essential for normal development of skeletal muscle.

Footnotes

↵ † V.W. and H.S. contributed equally to this work.
↵ ‡ To whom reprint requests should be addressed at: Abteilung Zellphysiologie, Max-Planck-Institut für medizinische Forschung, Jahnstrasse 29, 69120 Heidelberg, Germany.
↵ ¶ Permanent address: Physiologisches Institut, Universität Basel, 4051 Basel, Switzerland.
Bert Sakmann
Abbreviations: AChR, acetylcholine receptor; AChRɛ, acetylcholine receptor ɛ-subunit gene; mEPC, miniature end plate current; P, postnatal day; ES, embryonic stem.