Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies

Abstract

Patients with myasthenia gravis (MG) with antibodies to muscle-specific receptor tyrosine kinase (MuSK) differ from acetylcholine receptor (AChR)-positive MG patients, as they frequently present with severe oculobulbar muscle weakness or with neck, shoulder, and respiratory muscle involvement. The neuromuscular junction (NMJ) has been confirmed to be the main target of both AChR- and MuSK-MG. However, histopathological investigation disclosed that muscle fiber atrophy was prevalent in AChR-MG, whereas mild myopathic changes and mitochondrial abnormalities were more frequently observed in MuSK-MG. As the pathogenetic mechanism in MuSK-MG remains unclear, this study investigated the submicroscopic pattern of muscle histopathology to establish a possible correlation between clinical involvement and subcellular morphological findings. Muscle biopsies from seven MuSK-MG patients and from seven patients with AChR-MG were analyzed by transmission electron microscopy. Myopathic and mitochondrial abnormalities were more prominent in MuSK-MG and show giant, swollen, and degenerated mitochondria with fragmented cristae. The most common changes in AChR-MG muscles were fiber atrophy, myofibrillar disarray, and Z-line streaming, consistent with mild neurogenic abnormalities. A different pathogenetic mechanism is emerging in MuSK-MG compared to AChR-MG. Mitochondrial abnormalities seem to be more prominent in MuSK-MG, whereas neurogenic atrophy is observed in AChR-MG.

Ultrastructural Modifications in the Mitochondria of Hypoxia-Adapted Drosophila melanogaster

“…Cristae fragmentation and matrix swelling have been reported through a variety of perturbations [43], [44], [45], [46] including myocardial ischemia [47], [48]. The cristae fragmentation observed in our longitudinal sections produced an interesting honeycomb-like pattern in cross-section that was not observed in NC mitochondria (Figure 3).…”

Injection of a Soluble Fragment of Neural Agrin (NT-1654) Considerably Improves the Muscle Pathology Caused by the Disassembly of the Neuromuscular Junction

“…by immobilization, mechanical ventilation or by denervation, mitochondrial physiologic changes and/or breakdown are key elements for specific pathways inducing fiber atrophy. A possible involvement of the agrin/Lrp4/MuSK pathway in the physiological changes of the mitochondria has already been shown by [31] demonstrating swollen and irregularly shaped mitochondria in humans suffering from MuSK-dependent myasthenia gravis. Interestingly, this phenotype can also be observed for the mitochondria of SARCO mice ([24], refer to Fig 1K).…”

Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis

“…In skeletal muscle, MuSK is concentrated at the neuromuscular junction and plays a key role in the agrin-mediated formation, maintenance, and regeneration of postsynaptic specializations, including aggregates containing AChR and many other proteins [12][13][14]. The spectrum of clinical symptoms of MG with autoantibodies to AChR is comparable but not identical to those with autoantibodies to MuSK [11,15,16]. Moreover, autoantibodies against MuSK from MG patients inhibit agrinmediated aggregation of AChRs and reduce AChR expression in C2C12 cells in vitro, and upregulate muscle RING finger protein 1 (MuRF-1) in C2C12 cells in vitro as well as in muscle tissue in vivo and atrogin expression in TE671 cells in vitro, indicating muscle atrophy [8,[17][18][19].…”