check details Histological studies of the muscle tissues from the paretic rabbits, which had manifested severe exhaustion, revealed alterations in muscle fibers ranging from subtle to angular

atrophy intermingled with normal muscle tissue (Fig. ​(Fig.1B).1B). The histological changes typical of atrophied muscle fibers can result from MG, reduced mechanical ability or cachexia. In repetitive electromyograms from one of these paretic rabbits, the retroauricular branch of facial nerve was stimulated at 20 Hz, and recordings were taken from adjacent retroauricular muscle (Fig. ​(Fig.1C).1C). The compound muscle action potential (CMAP) showed a decremental pattern, Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical consistent with MG. However, injections of acetylcholine esterase inhibitor did not significantly reverse either the CMAP defect or the paralytic symptoms. Importantly, the induction of EAMG by MuSK antibodies is not confined to rabbit, as we and others can also elicit EAMG in mice by injection of MuSK protein (22). Figure Inhibitors,research,lifescience,medical 1 Rabbits manifest myasthenia gravis (MG)-like paresis after immunization with MuSK protein. (A) Two rabbits

representative of four animals with outcomes manifested myasthenic weakness after immunization with the recombinant MuSK protein. After three injections … How do antibodies to MuSK cause myasthenia? Next, we focused on demonstrating how MuSK antibodies cause MG. The pathogenicity of MuSK antibodies in MG has been questioned, since MuSK-positive patients with MG do not have a decrease in the number of AChRs nor is complement Inhibitors,research,lifescience,medical deposited at the NMJ of their biceps brachii muscles (20). Although the mechanisms of MG caused by AChR antibodies are well delineated, the same pattern does not Inhibitors,research,lifescience,medical necessarily apply to MG caused by MuSK antibodies. MuSK antibodies have been identified as predominantly of the IgG4 subclass, which does not activate complement.

However, the binding of MuSK antibodies to MuSK molecules could accelerate the latter’s degradation (antigenic modulation) and/or inhibit MuSK functions directly. MuSK is essential for AChR clustering at the developing NMJ, and its deficiency may lead to the complete loss of junctional ultrastructure (12, 13). To reveal the pathogenic role of MuSK antibodies in MG, we still need to know how MuSK acts at mature NMJ and whether MuSK is also of required for the maintenance of AChR clustering and the structural stability of mature NMJ. To elucidate the mechanisms of AChR clustering at NMJ, a number of studies were performed using cultured C2C12 myotubes. Agrin induces clustering of AChR in C2C12 myotubes following autophosphorylation by MuSK. In vitro, this event represents a major cascade of AChR clustering at the NMJ after innervation by motoneurons.