LRP4 Is Critical for Neuromuscular Junction Maintenance

Abstract

The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms.

Sclerostin/Receptor Related Protein 4 and Ginkgo Biloba Extract Alleviates β-Glycerophosphate-Induced Vascular Smooth Muscle Cell Calcification By Inhibiting Wnt/β-Catenin Pathway

“…A recent study found that Lrp4 may regulate bone balance by interacting with sclerostin, but how it regulates bone balance remains unclear [18]. Lrp4 is highly dependent on Lrp5/6 as a receptor for the neuroproteoglycansAgrin [19]. Chang et al [20] found that Lrp4 can promote sclerostin antagonistic WNT pathway and when the LRP4 gene is defective, the high bone mass is similar to that of patients with sclerostin.…”

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

“…In particular, conditional and/or inducible knockout techniques in mice reveal that NMJs disassemble and become functionally impaired upon loss of agrin, laminin-␤2 (375), Lrp4 (23), and MuSK (188,234). In humans, mutations in genes involved in NMJ function, such as those encoding AChR subunits, ColQ (resulting in the loss of AChE from the NMJ), Na v 1.4, or rapsyn are the most frequent cause of CMS (reviewed in Ref.…”

Muscle as a paracrine and endocrine organ

“…LRP4 is a single-pass transmembrane receptor that is targeted to the plasma membrane of skeletal muscle cells via secretory vesicle trafficking and interacts with nerve-derived agrin. Recent studies showed that conditional deletion of LRP4 from adult mouse skeletal muscle resulted in degeneration of both pre- and post-synaptic nerve terminals [14]. Indeed, within one month following LRP4 depletion, these mice exhibited phenotypes that resembled myasthenic syndromes including weight loss, muscle weakness, scoliosis, and premature death [14].…”