Muscle activity and muscle agrin regulate the organization of cytoskeletalproteins and attached acetylcholine receptor (AChR) aggregates in skeletalmuscle fibers

In innervated skeletal muscle fibers, dystrophin and beta -dystroglycan for m rib-like structures (costameres) that appear as predominantly transverse stripes over Z and M lines. Here, we show that the orientation of these str ipes becomes longitudinal in denervated muscles and transverse again in den ervated electrically stimulated muscles. Skeletal muscle fibers express non neural (muscle) agrin whose function is not well understood. In this work, a single application of greater than or equal to 10 nM purified recombinant muscle agrin into denervated muscles preserved the transverse orientation of costameric proteins that is: typical for innervated muscles, as did a si ngle application of greater than or equal to1 muM neural agrin. At lower co ncentration, neural agrin induced acetylcholine receptor aggregates, which colocalized with longitudinally oriented beta -dystroglycan, dystrophin, ut rophin, syntrophin, rapsyn, and beta2-laminin in denervated unstimulated fi bers and with the same but transversely oriented proteins in innervated or denervated stimulated fibers. The results indicate that costameres are plas tic structures whose organization depends on electrical muscle activity and /or muscle agrin.