Journal Article

Gamma-sarcoglycan is required for the response of archvillin to mechanical stimulation in skeletal muscle

Janelle M. Spinazzola, Tara C. Smith, Min Liu, Elizabeth J. Luna and Elisabeth R. Barton

in Human Molecular Genetics

Volume 24, issue 9, pages 2470-2481
Published in print May 2015 | ISSN: 0964-6906
Published online January 2015 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/ddv008
Gamma-sarcoglycan is required for the response of archvillin to mechanical stimulation in skeletal muscle

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Loss of gamma-sarcoglycan (γ-SG) induces muscle degeneration and signaling defects in response to mechanical load, and its absence is common to both Duchenne and limb girdle muscular dystrophies. Growing evidence suggests that aberrant signaling contributes to the disease pathology; however, the mechanisms of γ-SG-mediated mechanical signaling are poorly understood. To uncover γ-SG signaling pathway components, we performed yeast two-hybrid screens and identified the muscle-specific protein archvillin as a γ-SG and dystrophin interacting protein. Archvillin protein and message levels were significantly upregulated at the sarcolemma of murine γ-SG-null (gsg−/−) muscle but delocalized in dystrophin-deficient mdx muscle. Similar elevation of archvillin protein was observed in human quadriceps muscle lacking γ-SG. Reintroduction of γ-SG in gsg−/− muscle by rAAV injection restored archvillin levels to that of control C57 muscle. In situ eccentric contraction of tibialis anterior (TA) muscles from C57 mice caused ERK1/2 phosphorylation, nuclear activation of P-ERK1/2 and stimulus-dependent archvillin association with P-ERK1/2. In contrast, TA muscles from gsg−/− and mdx mice exhibited heightened P-ERK1/2 and increased nuclear P-ERK1/2 localization following eccentric contractions, but the archvillin–P-ERK1/2 association was completely ablated. These results position archvillin as a mechanically sensitive component of the dystrophin complex and demonstrate that signaling defects caused by loss of γ-SG occur both at the sarcolemma and in the nucleus.

Journal Article.  8643 words.  Illustrated.

Subjects: Genetics and Genomics

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