Restoration of γ-Sarcoglycan Localization and Mechanical Signal Transduction Are Independent in Murine Skeletal Muscle

Elisabeth R Barton

doi:10.1074/jbc.m109.063990

Abstract

Limb girdle muscular dystrophy 2C is caused by mutations in the gamma-sarcoglycan gene (gsg) that results in loss of this protein, and disruption of the sarcoglycan (SG) complex. Signal transduction after mechanical perturbation is mediated, in part, through the SG complex and leads to phosphorylation of tyrosines on the intracellular portions of the sarcoglycans. This study tested if the Tyr(6) in the intracellular region of gamma-sarcoglycan protein (gamma-SG) was necessary for proper localization of the protein in skeletal muscle membranes or for the normal pattern of ERK1/2 phosphorylation after eccentric contractions. Viral mediated gene transfer of wild type gsg (WTgsg) and mutant gsg lacking Tyr(6) (Y6Agsg) was performed into the muscles of gsg(-/-) mice. Muscles were examined for production and stability of the gamma-SG, as well as the level of ERK1/2 phosphorylation before and after eccentric contraction. Sarcolemmal localization of gamma-SG was achieved regardless of which construct was expressed. However, only expression of WTgsg corrected the aberrant ERK1/2 phosphorylation associated with the absence of gamma-SG, whereas Y6Agsg failed to have any effect. This study shows that localization of gamma-SG does not require Tyr(6), but localization alone is insufficient for restoration of normal signal transduction patterns after mechanical perturbation.

Highlights

Many of the limb girdle muscular dystrophies are caused by mutations in the sarcoglycans
We have been able to identify the SG complex as a player in the mechanical signal transduction process, where ␥-SG tyrosine phosphorylation occurs after a series of eccentric contractions, and disruption of the SG complex in mice lacking ␥-SG, which is a genetic model for limb girdle muscular dystrophies 2C, leads to an aberrant ERK1/2 response that is distinct from that observed in mdx mice in which the entire DGC is absent [5]
The goal of this study was to determine whether the mutation of Tyr6 in ␥-SG prevented proper localization of the protein to the sarcolemma or affected the normal signal transduction pathways following eccentric contractions

Summary

Introduction

Many of the limb girdle muscular dystrophies are caused by mutations in the sarcoglycans. We have been able to identify the SG complex as a player in the mechanical signal transduction process, where ␥-SG tyrosine phosphorylation occurs after a series of eccentric contractions, and disruption of the SG complex in mice lacking ␥-SG, which is a genetic model for limb girdle muscular dystrophies 2C, leads to an aberrant ERK1/2 response that is distinct from that observed in mdx mice in which the entire DGC is absent [5] Based on these findings, the SG complex has been proposed to be a mechanosensor, which can convert changes in load at the sarcolemma to distinct changes in gene expression and maintenance of muscle survival [6, 7]. The goal of this study was to test whether restoration of healthy muscle requires correct assembly of the sarcoglycan complex and whether post-translational modification of ␥-SG is important for mediating the intracellular response of skeletal muscle to mechanical load

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Results

Conclusion