γ-Sarcoglycan deficiency increases cell contractility, apoptosis and MAPK pathway activation but does not affect adhesion

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Abstract
The functions of γ-sarcoglycan (γSG) in normal myotubes are largely unknown, however γSG is known to assemble into a key membrane complex with dystroglycan and its deficiency is one known cause of limb-girdle muscular dystrophy. Previous findings of apoptosis from γSG-deficient mice are extended here to cell culture where apoptosis is seen to increase more than tenfold in γSG-deficient myotubes compared with normal cells. The deficient myotubes also exhibit an increased contractile prestress that results in greater shortening and widening when the cells are either lightly detached or self-detached. However, micropipette-forced peeling of single myotubes revealed no significant difference in cell adhesion. Consistent with a more contractile phenotype, acto-myosin striations were more prominent in γSG-deficient myotubes than in normal cells. An initial phosphoscreen of more than 12 signaling proteins revealed a number of differences between normal and γSG–/– muscle, both before and after stretching. MAPK-pathway proteins displayed the largest changes in activation, although significant phosphorylation also appeared for other proteins linked to hypertension. We conclude that γSG normally moderates contractile prestress in skeletal muscle, and we propose a role for γSG in membrane-based signaling of the effects of prestress and sarcomerogenesis.

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