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

Loss of gamma-sarcoglycan (gamma-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 gamma-SG-mediated mechanical signaling are poorly understood. To uncover gamma-SG signaling pathway components, we performed yeast two-hybrid screens and identified the muscle-specific protein archvillin as a gamma-SG and dystrophin interacting protein. Archvillin protein and message levels were significantly upregulated at the sarcolemma of murine gamma-SG-null (gsg(-/-)) muscle but delocalized in dystrophin-deficient mdx muscle. Similar elevation of archvillin protein was observed in human quadriceps muscle lacking gamma-SG. Reintroduction of gamma-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 gamma-SG occur both at the sarcolemma and in the nucleus.