Muscle Activity and Muscle Agrin Regulate the Organization of Cytoskeletal Proteins and Attached Acetylcholine Receptor (Achr) Aggregates in Skeletal Muscle Fibers

In innervated skeletal muscle fibers, dystrophin and β-dystroglycan form rib-like structures (costameres) that appear as predominantly transverse stripes over Z and M lines. Here, we show that the orientation of these stripes becomes longitudinal in denervated muscles and transverse again in denervated electrically stimulated muscles. Skeletal muscle fibers express nonneural (muscle) agrin whose function is not well understood. In this work, a single application of ≥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 single application of ≥1 μM neural agrin. At lower concentration, neural agrin induced acetylcholine receptor aggregates, which colocalized with longitudinally oriented β-dystroglycan, dystrophin, utrophin, syntrophin, rapsyn, and β2-laminin in denervated unstimulated fibers and with the same but transversely oriented proteins in innervated or denervated stimulated fibers. The results indicate that costameres are plastic structures whose organization depends on electrical muscle activity and/or muscle agrin.

• Publication year

  2001

• Venue

  Journal of Cell Biology

• Publication date

  2001-06-25

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1083/JCB.153.7.1453PMID 11425875PMCID 2150728
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2000influential reference
• Membrane skeleton of innervated and denervated fast‐ and slow‐twitch muscle

  2000cited by this paper
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  2000influential reference
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• Agrin Binds to the Nerve–Muscle Basal Lamina via Laminin

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• Muscular dystrophies and the dystrophin-glycoprotein complex.

  1997influential reference
• Agrin Binding to -Dystroglycan

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  1996influential reference
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  1995cited by this paper
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• Dystrophin and the membrane skeleton.

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  1990cited by this paper
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  1990cited by this paper
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  1989cited by this paper
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  1983cited by this paper
• Activity-dependent accumulation of basal lamina by cultured rat myotubes.

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