Abstract
Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs) studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs) with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones) and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4%) or complete (18%) failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR γ subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG.
Highlights
Autoimmune myasthenia gravis (MG) is a disorder that reduces the safety factor of neuromuscular transmission [1,2,3,4]
None of the muscle-specific tyrosine kinase (MuSK)-immunized mice died of myasthenia-related symptoms
To detect morphological alterations that could compromise neuromuscular transmission, we examined motor nerves labeled with antibodies to neurofilament or synaptophysin
Summary
Autoimmune MG is a disorder that reduces the safety factor of neuromuscular transmission [1,2,3,4]. The endplate acetylcholine receptor (AChR) was the only identified target for autoimmune MG until 2001, when Hoch and colleagues reported antibodies to MuSK in 70% of AChR-seronegative MG patients [5]. Subsequent studies, reported that 40 to 60% of AChR-seronegative patients had MuSK antibodies [6,7,8]. Bulbar and respiratory muscles are severely affected so that respiratory insufficiency is frequently observed in MuSK-MG patients [9, 10]. The non-responsiveness to AChE inhibitors, fluctuation of symptoms, and sparing of limb muscle hinders early diagnosis of MuSK-MG [12]. Long-term non-synaptic effects arising from reduced neuromuscular activity [19] may negatively impact the effectiveness of therapies that selectively target the NMJ. Improved understanding of the overall pathophysiology will improve MuSK-MG diagnosis and treatment as in the case of AChR-MG [20]
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